An approach to an enantioselective synthesis of crisamicin A via a novel double Hauser-Kraus annulation strategy

Article abstract of DOI:10.1016/j.tet.2008.02.065

A double Hauser-Kraus annulation between biscyanophthalide 4 and the d-mannose derived enone 39 provides access to an advanced intermediate 54 that is an excellent scaffold to effect an enantioselective total synthesis of crisamicin A 1.

Full text of DOI:10.1016/j.tet.2008.02.065

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3912e3927
www.elsevier.com/locate/tet
An approach to an enantioselective synthesis of crisamicin
A via a novel double HausereKraus annulation strategy
*
Olivier Andrey, Jonathan Sperry, Uffe S. Larsen, Margaret A. Brimble
Department of Chemistry, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 12 November 2007; received in revised form 4 February 2008; accepted 21 February 2008
Available online 26 February 2008
Abstract
A double HausereKraus annulation between biscyanophthalide 4 and the D-mannose derived enone 39 provides access to an advanced
intermediate 54 that is an excellent scaffold to effect an enantioselective total synthesis of crisamicin A 1.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyranonaphthoquinone antibiotics; Crisamicin A; HausereKraus annulation
1. Introduction
biscyanophthalide 4 and enone 5. This would give rise to the
double annulated product 3 that upon removal of the protect-
ing groups would undergo hydroxyl unmasking and in situ
intramolecular lactol formation under thermodynamic control
forming bis-cis-lactol 2. Silane mediated lactol reduction
followed by hydroquinone oxidation and treatment with Lewis
acid to remove the methyl ethers with concomitant epimeriza-
tion to the desired trans-ether would furnish crisamicin A 1.
The synthesis of monomeric quinone-containing natural
products using the HausereKraus annulation is widespread,8
but to date only one isolated example of a double Hausere
Kraus annulation has been reported during a total synthesis
of biphyscion,9 and a closely related double annulation has
been successfully employed during the total synthesis of
dimeric orsellinic acid derivatives.10 Notably, both of these
aforementioned routes employ cyclic enones as Michael
acceptors in the respective double annulation reactions, as
opposed to our proposed use of a chiral acyclic enone of
type 5.
The pyranonaphthoquinone (or isochromanquinone) family
of antibiotics exhibits activity against a variety of Gram-positive
bacteria, pathogenic fungi and yeasts,1,3b and has been proposed
to act as bioreductive alkylating agents.2 Whilst the synthesis of
monomeric members of this important family of antibiotics is
well documented,3 the enantioselective total synthesis of a natu-
rally occurring dimeric pyranonaphthoquinone antibiotic has yet
to be achieved.4 Herein we document our efforts towards an
asymmetric synthesis of a key dimeric pyranonaphthoquinone
antibiotic, crisamicin A (Fig. 1). Crisamicin A 1 was isolated
from the microorganism Micromonospora purpureochromo-
genes5 and exhibits activity against B16 murine melanoma cells,
and the herpes simplex and vesicular stomatitis viruses.6 To date,
the total synthesis of crisamicin A has yet to be achieved.
Our earlier synthetic work towards 1 utilized a novel furo-
furan annulation-oxidative rearrangement strategy, but this
route only facilitated access to regioisomers of crisamicin
A.4b,c Recently, our attention has focused on a new retrosyn-
thesis based around late stage construction of the pyran ring
(Scheme 1). It was envisioned that crisamicin A 1 could be
accessed via a key double HausereKraus annulation7 between
O
O
O
O
H
O
H
H
H
O
O
O
OH
OH
O
O
1
* Corresponding author. Tel.: þ64 9 3737599x88259; fax: þ64 9 3737599.
E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.065

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3913
O
O
O
O
OH
OH
OH
HO
OH
O
(i) lactol reduction
(ii) hydroquinone oxidation
(iii) Lewis acid
O
O
O
H
O
H
H
O
H
H
H
H
H
O
OH
O
OH
O
O
OMe
OMe OH
O
O
1
2
Removal of P
OH
O
O
OH
O
O
O
Hauser-Kraus
annulation
2 x
O
O
O
O
O
PO
O
O
NC
CN
OMe
OMe
OH OMe
OMe OH
O
PO
OP
4
5
3
P = protecting group
Scheme 1.
In order to test the viability of our approach, we first set out
to assess the ability of enones such as 5 to undergo Hausere
Kraus annulation with a monomeric phthalide. We chose the
4,6-dimethoxyphthalide 7 for this purpose as it possesses the
same substitution pattern on the aryl ring as biscyanophthalide
4, wherein the biaryl bond is replaced with a methoxy group.
To this end, formamide 6, prepared from 3,5-dimethoxyben-
zoic acid in three steps as previously described,11 was treated
with trimethylsilyl cyanide in the presence of catalytic quanti-
ties of potassium cyanide and 18-crown-612 to effect cycliza-
tion furnishing the desired dimethoxycyanophthalide 711 in
excellent yield (Scheme 2).
L-mannose, 5 g, NZ$600) would be conducted providing
enones with the correct absolute stereochemistry.
OH
O
O
O
HO
HO
(i)
OH
O
HO
8
9
Scheme 3. (i) HBr (30% in acetic acid) then Zn, AcOH, 7%.
Given that lactones possess relatively acidic protons
adjacent to the carbonyl, it was thought that this may have
a detrimental effect on the HausereKraus annulation as the
reaction is traditionally carried out in the presence of a strong
base. Therefore, the use of a suitably protected lactol was
deemed more compatible for the HausereKraus annulation
step and oxidation to the desired lactone could then be effected
after successful annulation.
With these ideas in mind attention focused on the synthesis of
methylacetal15, startingwithalarge-scaleiodine-mediatedpro-
tection of D-mannose to furnish the protected sugar 10.14 Chlori-
nation of 10 furnished 11 that underwent sodium-mediated
elimination followed by benzyl protection giving the known
furanoid glycal 12 in good yield.14 Unfortunately, all attempts
toeffect amercurymediatedglycosidationfollowedbyin siture-
duction of the carbonemercury bond led to facile elimination of
the intermediate 13 and the isolation of the ring opened product
14. None of the desired product 15 was obtained (Scheme 4).
In contrast, bromo-glycosidation of 12 furnished the
bromide 16 in good yield.15 Deprotection of 16 under acidic
conditions, followed by hydrogenation yielded diol 17.
Oxidative cleavage then afforded the aldehyde 18 that was
immediately subjected to a HornereWadswortheEmmons
olefination with diethyl (2-oxopropyl)phosphonate to give
the desired enone 19 containing a protected lactol functional-
ity (Scheme 5).
MeO
CO2H
MeO
CONEt2
CHO
3 steps
OMe
OMe
6
O
MeO
(i)
O
CN
OMe
7
Scheme 2. (i) TMS-CN, KCN, 18-c-6, CH2Cl2, 0 ꢀC, 2 h then AcOH, rt, 16 h,
98%.
With the synthesis of the monomeric model phthalide in
hand, attention next turned to the synthesis of a suitably
protected enone of type 5. It became clear from surveying
the literature that the best route to enone 5 was likely to be
a carbohydrate-derived synthesis. Unfortunately, a highly
promising report that D-glucono lactone 8 could be readily
transformed into lactone 913 could not be repeated in sufficient
yield or purity in our hands after numerous attempts (Scheme
3). Lactone 9 possesses the opposite absolute stereochemistry
to that of crisamicin A, but at this stage it was decided to lay
foundations for our proposed route and if it were successful,
the use of the expensive L-sugar (D-mannose 500 g, NZ$698;
Attention next focused on the key HausereKraus annula-
tion. Enone 19 and model phthalide 7 underwent annulation

3914
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
O
O
O
O
O
O
O
O
O
OH
Cl
O
O
(i)
O
(ii)
(iii)
(iv)
OMe
D-mannose
O
O
O
O
BnO
BnO
HgOAc
13
12
10
11
x
O
O
O
O
O
OH
OMe
+
12
BnO
OMe
BnO
14
15
Scheme 4. (i) I2, acetone, rt, 2 h, 85%; (ii) TsCl, Et3N, DMAP, CH2Cl2, rt; (iii) Na, naphthalene, THF, 0 ꢀC to rt then NaH, BnBr, Bu4NI, 0 ꢀC to rt, THF, 62% over
two steps; (iv) Hg(OAc)2, CaCO3, MeOHeTHF (1:1), 0 ꢀC, then KI, 15% (14/12¼1:4).
OH
O
HO
O
O
O
OHC
(i)
O
OMe
O
OMe
(ii)
(iii)
OMe
12
BnO
BnO
BnO
Br
16
18
17
O
O
(iv)
O
OMe
P(OEt)2
BnO
19
Scheme 5. (i) NBS, MeOHeMeCN, 0 ꢀC to rt, 69% (dr¼92:8); (ii) AcOHeH2O (4:1), 40 ꢀC then H2, Pd/C, Et3N, 62% over two steps; (iii) NaIO4, SiO2, CH2Cl2,
rt, 95% (crude); (iv) NaH, THF, 0 ꢀC to rt, 63%.
OH
O
MeO
O
OMe
H
O
OMe O
OH
O
O
MeO
HO
or
OH
MeO
O
21
O
OMe
(ii)
(i)
O
OMe
X
CN
OMe
BnO
19
H
MeO
OMe O
O
BnO
H
7
20
H
OMe OH
O
OMe
22
Scheme 6. (i) KOtBu, DMSO, rt, 78% (dr¼65:35); (ii) H2, Pd/C, EtOAc, rt.
with potassium tert-butoxide in dimethylsulfoxide, resulting in
formation of the non-aromatized adduct 20 as a 65:35 mixture
of diastereomers. The stereochemistry of the major product
was not determined. Unfortunately, attempted unmasking of
the hydroxyl group via hydrogenation did not afford either de-
protected alcohol 21 or tetrahydropyran derivative 22, and
only decomposition was observed (Scheme 6).
At this stage it was decided to change the protecting group
from benzyl ether 19 to silyl ether 27 (Scheme 7). Thus,
sodium-mediated elimination of chloride 11 followed by silyl-
ation gave the tert-butyldiphenylsilyl ether 23 that underwent
smooth bromo-glycosidation delivering bromide 24. Aceto-
nide removal under acidic conditions, followed by hydrogena-
tion yielded the diol 25. Sodium periodate mediated oxidative

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3915
OH
O
O
HO
O
O
O
O
OHC
O
O
OMe
OMe
(iv)
(iii)
(i)
OMe
(ii)
11
TBDPSO
TBDPSO
Br
TBDPSO
TBDPSO
23
26
25
24
O
O
O
(v)
P(OEt)2
O
OMe
TBDPSO
27
Scheme 7. (i) Na, naphthalene, THF, 0 ꢀC to rt then TBDPSCl, imidazole, CH2Cl2, 0 ꢀC to rt, 59% over two steps; (ii) NBS, MeOHeMeCN, 0 ꢀC to rt, 87%
(dr¼84:16); (iii) AcOHeH2O (4:1), 40 ꢀC then H2, Pd/C, Et3N, 23% over two steps; (iv) NaIO4, SiO2, CH2Cl2, rt, 100%; (v) NaH, THF, 0 ꢀC to rt, 63%.
O
MeO
O
OH
O
OH
O
MeO
MeO
CN
OMe
(i)
(iii) X
(ii)
O
O
22
OMe
OMe
7
8
O
H
OMe O
28
H
HO
OMe O
O
OMe
OTBDPS
29
TBDPSO
27
Scheme 8. (i) KOtBu, DMSO, rt, 66%; (ii) TBAF, DMF, rt, 52%; (iii) Et3SiH, TFA, CH2Cl2, ꢁ78 ꢀC to 0 ꢀC.
cleavage then gave aldehyde 26 that was immediately
subjected to HornereWadswortheEmmons olefination deliv-
ering the desired enone 27 (Scheme 7). HausereKraus annu-
lation between enone 27 and model phthalide 7 was next
performed, again resulting in the formation of non-aromatized
adduct 28 as a single diastereomer. Treatment of 28 with
tetrabutylammonium fluoride gave a more polar product
thought to be 29 upon analysis of the crude reaction mixture
Thus, the synthesis of the PMB-protected enone 35 was
undertaken. Use of para-methoxybenzyl alcohol (PMBOH)
in the bromo-glycosidation step furnished the desired adduct
32. After acid mediated acetonide deprotection, use of the
radical initiator Et3BeO2 at ꢁ78 ꢀC effected debromination
to furnish the diol 33 in excellent yield. Oxidative cleavage
and immediate olefination of aldehyde 34 gave the desired
enone 35 (Scheme 10). PMB-protected enone 35 then under-
went smooth HausereKraus annulation with phthalide 7
giving the non-aromatized product 36 as a single diastereomer.
However, all attempts to remove the PMB group under neutral
1
by H NMR. However, all attempts to form the desired pyran
product 22 from the crude reaction mixture led to degradation
(Scheme 8).
At this stage it was thought that effecting aromatization of
the adduct 28 prior to further manipulation would facilitate
future steps in the synthesis. Attempts to rearomatize 28, in-
cluding the use of several bases in the presence of dimethyl
sulfate (to trap the resulting hydroquinone), TBDPSCl and
2,6-lutidine, or tosic acid led to recovered 28. Various oxidants
were also tried in an attempt to isolate the quinone, also to no
avail. Unfortunately, treatment with acid promoted elimination
to dihydronaphthoquinone 31 as the sole product (Scheme 9).
This observation suggests that the presence of the methoxy
group on the lactol prevents the desired aromatization from
taking place and the tetrahydrofuran ring eliminates faster
than the product tautomerizes to the stable aromatic enol
form. Based on this observation, it was decided to prepare
an enone in which the lactol was protected so that it could
be liberated under non-acidic conditions and hence does not
eliminate to compounds of type 31 during aromatization.
OH
O
OH
O
MeO
MeO
O
O
x
OMe
OMe
H
OMe OH
H
OMe O
HO
OTBDPS
30
28
H+
OH
O
OH
O
MeO
MeO
O
H
OMe
8
OMe O
H+
OMe OH
OTBDPS
31
Scheme 9.

3916
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
OH
O
HO
O
O
O
OHC
O
OPMB
OPMB
(iii)
(ii)
OPMB
(i)
23
TBDPSO
TBDPSO
33
Br
TBDPSO
34
32
O
O
(iv)
O
P(OEt)2
O
OPMB
TBDPSO
35
Scheme 10. (i) NBS, PMBOH, MeCN, 0 ꢀC to rt, 72% (dr¼84:16); (ii) AcOHeH2O (4:1), 40 ꢀC then Bu3SnH, Et3B, air, CH2Cl2, ꢁ78 ꢀC, 83% over two steps;
(iii) NaIO4, SiO2, CH2Cl2, rt, 100% (crude); (iv) NaH, THF, 0 ꢀC to rt, 63%.
O
OH
O
OH
O
O
MeO
MeO
MeO
O
OPMB
O
(i)
(ii) X
O
O
OPMB
OH
CN
OMe
TBDPSO
35
H
OMe O
H
OMe O
37
OTBDPS
OTBDPS
7
36
Scheme 11. (i) KOtBu, DMSO, rt, 53%; (ii) DDQ, CH2Cl2eH2O (19:1).
oxidative conditions (DDQ, phosphate buffer) failed, with
only starting material being isolated (Scheme 11). To circum-
vent this problem, it was decided to remove the PMB group
and effect oxidation to the lactone prior to the annulation
step and hence conduct the HausereKraus annulation with
lactone instead of a protected lactol. Thus, oxidative removal
of the PMB group in 35 with DDQ under buffered conditions
furnished lactol 38 that underwent smooth PCC mediated
oxidation to the lactone 39 (Scheme 12).
determined by 1H NMR spectroscopy. Although silica gel
chromatography did not allow separation of the two com-
pounds, it did facilitate further cyclization of 42 to 43 giving
a ratio of 1:4 in favour of the cyclized product 43, as deter-
1
mined by H NMR spectroscopy. The structure of 43 was
also postulated to exist as a single cis-diastereomer from
spectroscopic studies presumably as fluoride-induced depro-
tection of 41 liberates the hydroxyl group, which undergoes
cyclization under thermodynamic control.16a
Gratifyingly, lactone 39 underwent smooth HausereKraus
annulation with phthalide 7 to give the non-aromatized
product 40 in excellent yield as a single diastereomer. Aroma-
tization could be successfully achieved upon exposure to
boron trifluoride etherate followed by immediate trapping of
the resulting unstable hydroquinone with acetic anhydride,
affording the aromatized, stable monoacetate 41 in 53% yield
over two steps after flash chromatography. Exposure of 41 to
HFepyridine gave an inseparable mixture of uncyclized (42)
and cyclized cis-lactol (43) products in a 4:1 ratio as
For the synthetic route to progress, CAN oxidation of the
crude mixture of 42/43 (4:1, pre-silica treatment) was neces-
sary, affording quinone 44 in 38% yield over two steps from
monoacetate 41. Cyclization of 44 and concomitant triethylsi-
lane mediated reduction16b successfully reduced the interme-
diate lactol in a stereospecific manner, but unfortunately
none of the desired product 45 was obtained. Rather, carboxy-
lic acid 46 formed wherein ring opening of the lactone moiety
had taken place. Attempted recyclization of acid 46 based on
the literature precedent17 using methanol and oxygen only af-
forded the methyl ester 47 (Scheme 13). Despite this, an enan-
tioselective route to a monomer closely related to the
crisamicins had been achieved.
O
O
O
O
OPMB
OH
At this stage, synthetic studies were directed towards the
dimeric structure. Our attention therefore turned to the synthe-
sis of the key biscyanophthalide 4.
(i)
TBDPSO
TBDPSO
38
35
Thus, 3,5-dimethoxybenzoic acid was converted to the
diethylamide 48,18 which was selectively monodeprotected
with boron tribromide at high dilution in dichloromethane.
The resulting phenol 49 was then readily converted to triflate
50. After much optimization, it was found that treatment of
a dioxane solution of triflate 50 with precisely 0.5 equiv of
bis(pinacolato)diboron, freshly ground dried potassium car-
bonate under Pd(dppf)Cl2 catalysis at 100 ꢀC for 3 h resulted
(ii)
O
O
O
TBDPSO
39
Scheme 12. (i) DDQ, CH2Cl2eH2O (19:1), pH¼7, 78% (anti/syn¼56:44); (ii)
˚
PCC, NaOAc, MS 4 A, 91%.

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3917
O
MeO
O
OAc O
OH
O
O
MeO
MeO
(ii)
CN
(i)
OMe
O
O
O
O
H
7
H
MeO HO
MeO
MeO
O
OTBDPS
OTBDPS
40
O
O
(iii)
41
TBDPSO
39
OAc O
OAc
H
OH
O
O
MeO
MeO
O
+
H
O
O
(v)
(iv)
O
O
O
42:43
(4:1)
H
MeO HO
MeO
HO
O
H
MeO
O
OH
OH
43
42
44
42:43 4:1
42:43 1:4 after chromatography
O
O
O
O
MeO
MeO
MeO
O
O
O
(vi)
H
O
CO2Me
H
MeO
HO
O
MeO
O
MeO
O
O
47
46
45
Scheme 13. (i) KOtBu, DMSO, rt, 80%; (ii) BF3$Et2O, CH2Cl2, ꢁ78 ꢀC to 0 ꢀC then Ac2O, py, ꢁ10 ꢀC to rt, 53% over two steps; (iii) HF$Py, THF, rt, then SiO2
(42/43¼4:1); (iv) CAN, MeCNeH2O (2:1), 38% from 41; (v) BF3$Et2O (10 equiv), Et3SiH (10 equiv), CH2Cl2, ꢁ78 ꢀC to rt, 63%; (vi) MeOH, O2, dark, 32%.
in a quantitative yield of the homocoupled product 51 in a one-
pot, one-step operation. Next, the combined directing ability
of the methoxy and the diethylamide functionalities facilitated
dilithiation followed by treatment with dimethylformamide to
afford the bisformyl derivative 52 in excellent yield. Subse-
quent biscyanophthalide formation then gave 4, also in good
yield (Scheme 14).
diacetate 54, albeit in 23% yield over the two steps. To the
best of our knowledge, this result represents the first successful
double HausereKraus annulation using an acylic Michael
acceptor (Scheme 15).
2. Conclusions
Finally, attention focused on the key double HausereKraus
annulation, based on the successful model annulation between
monomeric cyanophthalide 7 and enone 39. Thus, the dianion
of biscyanophthalide 4 generated with excess potassium tert-
butoxide was treated with 2 equiv of enone 39 providing the
highly unstable adduct 53 that was immediately subjected to
our established acetylation protocol, gratifyingly providing
The synthesis of an advanced intermediate 54 that provides
an excellent basis for an asymmetric total synthesis of crisami-
cin A has been achieved. Key steps included construction of
the biaryl bond using a one-pot, one-step SuzukieMiyaura
homocoupling and a double HausereKraus annulation be-
tween a biscyanophthalide 4 and a carbohydrate (mannose) de-
rived acyclic enone 39. Difficulties encountered in performing
MeO
CO2H
HO
CONEt2
CONEt2
MeO
TfO
CONEt2
(iii)
(ii)
(i)
OMe
OMe
OMe
OMe
50
48
49
O
O
(iv)
CONEt2
CHO
CONEt2
O
O
(vi)
2
(v)
2
NC
CN
OMe
OMe
OMe
OMe
52
4
51
Scheme 14. (i) SOCl2, CH2Cl2, rt, 16 h then HNEt2, CH2Cl2, 0 ꢀC to rt, 2 h, 71%; (ii) BBr3, CH2Cl2, ꢁ78 ꢀC, 1 h, 72%; (iii) PhN(OTf)2, Et3N, DMAP, CH2Cl2,
0 ꢀC to rt, 3 h, 89%; (iv) Pd(dppf)Cl2, dppf, K2CO3, bis(pinacolato)diboron, dioxane, 100 ꢀC, 3 h, 100%; (v) tBuLi (4 equiv), TMEDA, THF, ꢁ78 ꢀC, then DMF, rt,
16 h, 92%; (vi) TMS-CN, KCN, 18-c-6, CH2Cl2, 0 ꢀC, 2 h then AcOH, rt, 16 h, 81%.

3918
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
O
OH
OH
O
O
O
O
(i)
O
O
O
O
O
O
O
NC
CN
TBDPSO
H
H
O
OMe
OMe
OMe O
TBDPSO
OMe
53
O
OTBDPS
39
4
(2.2 eq.)
O
OAc
(ii)
O
H
OAc
O
O
O
O
H
OMe
OH
OMe OH
TBDPSO
OTBDPS
54
Scheme 15. (i) KOtBu, DMSO, rt; (ii) BF3$Et2O, CH2Cl2, ꢁ78 ꢀC to 0 ꢀC then Ac2O, py, ꢁ10 ꢀC to rt, 23% over two steps.
the double annulation reaction on a large scale and good yield
have so far prevented the conversion of biaryl 54 to crisamicin
A and work towards this end is ongoing.
3.1.1. 3-Cyano-5,7-dimethoxy-(3H)-isobenzofuran-1-one
(7)11
N,N-Diethyl 2,4-dimethoxy-6-formylbenzamide 6 (234 mg,
0.87 mmol) was taken up in dichloromethane (5 mL) and
cooled to 0 ꢀC. Trimethylsilyl cyanide (0.13 mL, 1.1 equiv,
0.95 mmol) was added followed by potassium cyanide
(6 mg, 0.1 equiv, 0.09 mmol) and 18-crown-6 (10 mg). The
reaction mixture was stirred at 0 ꢀC for 1.5 h then at room tem-
perature for 30 min. The reaction mixture was concentrated in
vacuo and the residue taken up in acetic acid (5 mL) and
stirred at room temperature for 16 h. Sodium hydroxide
(1 M, 10 mL) was added, followed by ethyl acetate (20 mL).
The layers were separated and the aqueous layer extracted
with ethyl acetate (3ꢂ20 mL). The combined organic extracts
were dried over anhydrous sodium sulfate, filtered and concen-
trated in vacuo. The resulting residue was purified by flash
chromatography eluting with hexaneseethyl acetate (3:1) to
afford the title compound 7 as a colourless solid (330 mg,
66%), mp 132e133 ꢀC (lit.11 134e135 ꢀC). dH (300 MHz,
CDCl3) 6.66 (1H, d, J 1.7, CH), 6.54 (1H, d, J 1.7, CH),
5.91 (1H, s, CH), 3.98 (3H, s, OMe), 3.94 (3H, s, OMe). Spec-
troscopic data consistent with the literature.11
3. Experimental
3.1. General
All reactions were carried out in flame or oven dried glass-
ware under a dry nitrogen atmosphere. Tetrahydrofuran and
diethyl ether were dried over sodium wire. Dichloromethane,
pyridine and triethylamine were dried over calcium hydride,
and ethanol and methanol were dried over magnesium ethox-
ide and methoxide, respectively. All solvents were distilled
prior to use. Flash chromatography was carried out using
0.063e0.1 mm silica gel with the desired solvent. Thin layer
chromatography was performed using silica coated aluminium
plates (60 F254). Compounds were identified using UV fluores-
cence and/or staining with vanillin in methanolic sulfuric acid,
a solution of ammonium heptamolybdate and cerium sulfate in
aqueous sulfuric acid, iodine or a solution of potassium
permanganate and potassium carbonate in aqueous sodium
hydroxide. Low resolution mass spectra were recorded using
a VG-70SE spectrometer operating at a nominal accelerating
voltage of 70 eV. High resolution mass spectra were recorded
at a nominal resolution of 5000e10,000. Infrared spectra were
obtained using a PerkineElmer Spectrum 1000 series Fourier
Transform IR spectrometer as a thin film between sodium
chloride plates. NMR spectra were recorded on either a Bruker
DRX300 spectrometer operating at 300 MHz for 1H nuclei and
75 MHz for 13C nuclei or using a Bruker DRX400 spectrom-
3.1.2. (3aS,4S,6R,6aS)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-
yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]-
dioxol-4-ol (10)14
To a suspension of D-mannose (15 g, 83.3 mmol) in acetone
(0.75 L) was added iodine (4.3 g, 16.8 mmol) and the mixture
was stirred for 2 h at room temperature. The reaction mixture
was quenched at 0 ꢀC with sodium thiosulfate (200 mL) and
sodium bicarbonate (200 mL) then extracted with chloroform
(500 mL). After three washings with sodium bicarbonate, the
organic layer was dried over MgSO4, filtered and concentrated
in vacuo to give the title compound as a pale yellow solid
(19.2 g, 89%), which was used without further purification
in the next step. dH (400 MHz, CDCl3) 5.38 (1H, d, J 2.4,
CH), 4.81 (1H, dd, J 6.0, 3.6, CH), 4.62 (1H, d, J 6.0, CH),
4.40e4.38 (1H, m, CH), 4.18 (1H, dd, J 7.2, 3.6, CH),
4.06e3.99 (2H, m, CH2), 2.57 (1H, br s, CH), 1.46 (3H, s,
eter operating at 400 MHz for 1H nuclei and 100 MHz for 13
C
1
nuclei. H NMR data is reported as chemical shift, relative
integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
quint., quintet), coupling constant (J in hertz) and assignment.
Optical rotations were measured using a PerkineElmer 341
polarimeter at l¼598 nm and are given in 10ꢁ1 deg cm2 gꢁ1
.
Melting points were determined on a Kofler hot-stage appara-
tus and are uncorrected.

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3919
Me), 1.45 (3H, s, Me), 1.38 (3H, s, Me), 1.32 (3H, s, Me); dC
(100 MHz, CDCl3) 112.4, 108.9, 100.9, 85.3, 79.9, 79.5, 73.2,
66.3, 26.7, 25.8, 25.1. 24.4. Spectroscopic data consistent with
the literature.14
11). dH (400 MHz, CDCl3) 7.32e7.24 (5H, m, AreH), 6.62
(1H, d, J 2.4, CH), 5.29 (1H, t, J 2.8, CH), 4.66e4.62 (1H,
m, CH), 4.55e4.46 (3H, m, 3ꢂCH), 4.44 (1H, dd, J 5.2,
4.4, CH), 4.12e4.09 (1H, m, CH), 3.99e3.94 (1H, m, CH),
1.47 (3H, s, Me), 1.40 (3H, s, Me); dC (100 MHz, CDCl3)
150.3, 138.2, 128.1, 127.4, 127.3, 108.5, 101.7, 83.9, 79.1,
73.0, 70.9, 65.9, 26.6, 25.3. Spectroscopic data consistent
with the literature.14
3.1.3. (3aS,4R,6R,6aS)-4-Chloro-6-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]-
dioxole (11)14
To a solution of bisacetonide 10 (6.5 g, 25.0 mmol) in
dichloromethane (150 mL) were added successively at room
temperature, DMAP (1.83 g, 15.0 mmol), tosyl chloride
(5.72 g, 30.0 mmol) and triethylamine (3.5 mL, 25.0 mmol).
After 3 h stirring at room temperature, the solution was hydro-
lyzed with sodium bicarbonate (100 mL) and then extracted
with diethyl ether (3ꢂ100 mL). The combined organic layers
were washed with saturated copper sulfate (100 mL) and brine
(2ꢂ50 mL), dried over MgSO4, filtered and concentrated in
vacuo to give a pale yellow oil. Purification by flash chroma-
tography on silica gel eluting with hexaneseethyl acetate (9:1)
gave the title compound as a viscous amber-coloured oil (4.3 g,
62%). dH (400 MHz, CDCl3) 6.07 (1H, s, CH), 4.96 (1H, d,
J 5.6, CH), 4.89e4.87 (1H, m, CH), 4.44e4.40 (1H, m,
CH), 4.21 (1H, dd, J 11.2, 3.6, CH), 4.10 (1H, dd, J 8.8,
6.0, CH), 4.02 (1H, dd, J 8.8, 4.4, CH), 1.47 (3H, s, Me),
1.46 (3H, s, Me), 1.39 (3H, s, Me), 1.33 (3H, s, Me); dC
(100 MHz, CDCl3) 113.2, 109.4, 97.5, 89.1, 82.3, 78.5, 72.3,
66.7, 27.0, 25.9, 25.2, 24.7. Spectroscopic data consistent
with the literature.14
3.1.5. (E,1S,2R)-2-(Benzyloxy)-4-methoxy-1-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol (14)
To a solution of glycal 12 (100 mg, 0.36 mmol) in a mixture
of THFemethanol (1:1, 4 mL) was added mercury diacetate
(138 mg, 0.43 mmol) at room temperature. After 2.5 h the mix-
ture was diluted with diethyl ether and treated with 2.5 M aque-
ous potassium iodide (10 mL). The mixture was decanted and
the organic layer was washed with saturated sodium thiosulfate,
brine, dried over MgSO4, filteredand concentrated invacuo. The
residue was purified by flash chromatography on silica gel
eluting with hexaneseethyl acetate (8:2) to give the recovered
starting material 12 (77 mg, 77%) and the title compound as
a colourless oil (17 mg, 15%). nmax (film) 3160, 2963, 1699,
1450, 1354, 1283, 1167, 1110, 741 cmꢁ1; dH (400 MHz,
CDCl3) 7.30e7.26 (5H, m, AreH), 6.56 (1H, d, J 12.8, H-4),
4.85 (1H, dd, J 12.8, 9.5, H-3), 4.63 (1H, d, J 11.8, OCHAHBPh),
4.37 (1H, d, J 11.8, OCHAHBPh), 4.16 (1H, q, J 6.4, H-40), 4.04
(1H, dd, J 8.4, 6.2, HAHB-50), 3.98 (1H, dd, J 8.4, 6.3, HAHB-50),
3.87 (1H, dd, J 9.5, 3.5, H-2), 3.59 (3H, s, OMe), 3.57 (1H, dt,
J 7.0, 3.5, H-1), 2.47 (1H, d, J 7.4, OH), 1.40 (3H, s, C20-
CAH3), 1.35 (3H, s, C20-CBH3); dC (100 MHz, CDCl3) 152.0,
138.3, 128.4 (2C), 127.8 (2C), 127.6, 109.0, 99.2, 76.4, 75.8,
75.6, 69.2, 66.3, 56.0, 26.7, 25.5; m/z (CI, NH3) 309 (MHþ, 1),
219 (10), 201 (40), 169 (25), 143 (13), 128 (29), 127 (45), 111
(41), 108 (29), 101 (100), 91 (41), 73 (38), 71 (15); HRMS
(CI) MHþ; found: 309.1696. C17H25O5 requires: 309.1702.
3.1.4. (R)-4-((2S,3R)-3-(Benzyloxy)-2,3-dihydrofuran-2-yl)-
2,2-dimethyl-1,3-dioxolane (12)14
To a solution of naphthalene (5.93 g, 46.3 mmol) in dry
THF (300 mL) were added at room temperature small pieces
of sodium (3.55 g, 154.3 mmol) previously dipped in methanol
and rinsed with diethyl ether. After 20 min the solution turned
deep green and the stirring was continued for 1.5 h. A solution
of compound 11 (4.3 g, 15.4 mmol) in dry THF (50 mL) was
then added at 0 ꢀC over 5 min. The reaction mixture was
allowed to warm up to room temperature and after stirring
for 10 min, the mixture was carefully hydrolyzed with water
(25 mL) then poured into diethyl ether (300 mL). After wash-
ing with brine, dried using MgSO4, filtered and concentrated
in vacuo afforded the crude alcohol as a pale yellow oil for
use directly in the next step without further purification. To
a suspension of sodium hydride (95%, 507 mg, 20.1 mmol)
in THF (20 mL) was added at 0 ꢀC a solution of the crude
alcohol (15.4 mmol) in THF (30 mL). After 15 min at 0 ꢀC,
benzyl bromide (2.4 mL, 20.1 mmol) and tetrabutylammo-
nium iodide (285 mg, 0.77 mmol) were added. The reaction
mixture was allowed to warm to room temperature and stirred
for 2 h. The reaction was hydrolyzed with water and extracted
with diethyl ether (3ꢂ50 mL). The combined organic layers
were washed with sodium bicarbonate and brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel eluting with
hexaneseethyl acetate (95:5/4:1) to afford the title com-
pound as a pale yellow oil (3.44 g, 62% over two steps from
3.1.6. (R)-4-((2R,3S,4R,5R)-3-(Benzyloxy)-4-bromo-
tetrahydro-5-methoxyfuran-2-yl)-2,2-dimethyl-1,3-
dioxolane (16)
To a solution of glycal 12 (297 mg, 1.09 mmol) and methanol
(0.44 mL, 10.9 mmol) in acetonitrile (5 mL) was added N-bro-
mosuccinimide (204 mg, 1.14 mmol) at 0 ꢀC. The solution
was stirred for 1 h at room temperature and the solventwas evap-
orated. The residue was dissolved in dichloromethane (15 mL),
washed with saturated sodium thiosulfate, brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography eluting with hexaneseethyl
acetate (9:1) to give the title compound as a colourless oil
(293 mg, 69%, dr 92:8). Major diastereomer: nmax (film) 2978,
2929, 1450, 1368, 1251, 1209, 1152, 1109, 1049, 957, 851,
737 cmꢁ1; dH (400 MHz, CDCl3) 7.36e7.27 (5H, m, AreH),
5.17 (1H, s, H-50), 4.71 (1H, d, J 12.0, OCHAHBPh), 4.56 (1H,
d, J 12.0, OCHAHBPh), 4.51 (1H, dd, J 6.1, 5.0, H-20), 4.39
(1H, q, J 6.3, H-4), 4.19 (1H, dd, J 4.8, 0.8, H-30), 4.13 (1H, s,
H-40), 4.10 (1H, dd, J 8.6, 6.3, HAHB-5), 4.05 (1H, dd, J 8.6,
6.3, HAHB-5), 3.41 (3H, s, OMe), 1.45 (3H, s, C2-CAH3), 1.38
(3H, s, C2-CBH3); dC (100 MHz, CDCl3) 137.3, 128.4 (2C),

3920
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
127.9, 127.8 (2C), 110.7, 108.8, 83.8, 82.0, 73.8, 72.3, 66.8,
55.9, 50.1, 26.7, 25.4; m/z (CI, NH3) 389 (MHþ, 4), 387
(MHþ, 4), 316 (7), 315 (7), 299 (13), 297 (13), 173 (26), 149
(22), 132 (12), 111 (13), 108 (27), 101 (59), 91 (100); HRMS
7.27 (5H, m, AreH), 6.93 (1H, dd, J 16.4, 6.2, H-4), 6.29 (1H,
dd, J 16.0, 1.6, H-3), 5.08 (1H, dd, J 5.6, 2.4, H-50), 4.63 (1H,
dt, J 6.0, 1.2, H-20), 4.54 (1H, d, J 12.8, OCHAHBPh), 4.46
(1H, d, J 12.8, OCHAHBPh), 4.21e4.17 (1H, m, H-30), 3.46
(3H, s, OMe), 2.30 (3H, s, H-1), 2.30e2.14 (2H, m, H-40); dC
(100 MHz, CDCl3) 198.5, 143.9, 137.6, 131.8, 128.4 (2C),
127.8, 127.6 (2C), 105.2, 81.3, 78.3, 71.7, 55.9, 38.3, 26.9; m/
z (EI) 276 (Mþ, 1), 190 (17), 146 (10), 99 (18), 92 (17), 91
(100), 87 (70), 65 (11), 59 (64), 43 (16); HRMS (EI) Mþ; found:
276.1362. C16H20O4 requires: 276.1362.
(CI) MHþ; found: 389.0790, 387.0812. C17H BrO5,
81
24
79
C17H BrO5 requires: 389.0787, 387.0807.
24
3.1.7. (R)-1-(2R,3R,5R)-3-(Benzyloxy)tetrahydro-5-
methoxyfuran-2-yl-ethane-1,2-diol (17)
Compound 16 (304 mg, 0.78 mmol) was stirred for 16 h at
room temperature in 60% aqueous acetic acid (25 mL). Azeo-
tropic removal of the acetic acid with toluene under reduced
pressure gave the crude bromo-diol as a colourless oil. The res-
idue was dissolved in methanol (3 mL), then treated with
triethylamine (0.15 mL) and Pd/C 10% (83 mg, 0.078 mmol).
The mixture was vigorously stirred under a hydrogen atmo-
sphere (1 atm) for 20 h, then filtered through a pad of CeliteÒ
and concentrated in vacuo. The residue was purified by flash
chromatography eluting with hexaneseethyl acetate (1:1) to
give the title compound as a colourless oil (130 mg, 62%) for
use immediately in the next step. nmax (film) 3413, 2920,
1494, 1450, 1353, 1208, 1038, 941, 735, 699 cmꢁ1; dH
(400 MHz, CDCl3) 7.39e7.29 (5H, m, AreH), 5.00 (1H, dd, J
4.8, 3.2, H-50), 4.71 (1H, d, J 11.6, OCHAHBPh), 4.41 (1H, d,
J 11.6, OCHAHBPh), 4.33 (1H, dt, J 5.8, 4.0, H-1), 4.07e4.01
(2H, m, H-20 and H-30), 3.85 (1H, dd, J 11.2, 2.8, HAHB-2),
3.72 (1H, dd, J 11.2, 5.2, HAHB-5), 3.37 (3H, s, OMe), 3.19
(1H, br s, OH), 2.23e2.04 (3H, m, H-40 and OH); dC
(100 MHz, CDCl3) 137.2, 128.7 (2C), 128.1, 127.8 (2C),
105.0, 80.1, 78.2, 71.7, 70.8, 64.3, 55.5, 37.3; m/z (CI, NH3)
286 (MþNHþ4 , 11), 254 (100), 237 (27), 129 (15), 111 (38),
108 (20), 100 (19), 91 (53); HRMS (CI) MþNHþ4 ; found:
286.1650. C14H24NO5 requires: 286.1655.
3.1.9. 3-Acetyl-2-((2R,3R,5R)-3-(benzyloxy)tetrahydro-5-
methoxyfuran-2-yl)-4-hydroxy-6,8-dimethoxynaphthalen-
1(2H)-one (20)
To a solution of 1,3-dihydro-5,7-dimethoxy-3-oxoisobenzo-
furan-1-carbonitrile 7 (26 mg, 0.121 mmol) and enone 19
(40 mg, 0.145 mmol) in DMSO (5 mL) was added dropwise
a solution of potassium tert-butoxide (19 mg, 0.157 mmol)
in DMSO (3 mL). After 30 min the orange solution was
cooled in an ice bath, diluted with diethyl ether (5 mL) and
quenched with saturated ammonium chloride. The mixture
was decanted and the aqueous layer was extracted three times
with diethyl ether. The combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated in
vacuo to give a yellow oil. Purification by flash chromatogra-
phy eluting with hexaneseethyl acetate (6:4/4:6) gave the
title compound as a yellow oil (44 mg, 78%, dr¼65:35). Major
diastereomer: nmax (film) 2919, 2843, 1784, 1680, 1587, 1337,
1240, 1216, 1160, 1087, 1052, 941, 733 cmꢁ1; dH (400 MHz,
CDCl3) 7.51e7.49 (2H, m, AreH), 7.37e7.26 (3H, m,
AreH), 7.23 (1H, d, J 2.4, H-5), 6.60 (1H, d, J 2.4, H-7),
4.92 (1H, dd, J 6.5, 1.3, H-50), 4.70 (2H, s, OCH2Ph), 4.44
(1H, d, J 9.1, H-2), 4.00e3.88 (2H, m, H-20 and H-30), 3.93
(3H, s, AreOMe), 3.90 (3H, s, AreOMe), 3.34 (3H, s,
C50-OMe), 2.41 (3H, s, COMe), 2.25e2.00 (2H, m, H2-40);
dC (100 MHz, CDCl3) 201.3, 194.9, 167.7, 164.9, 161.1,
138.4, 128.24, 128.17 (2C), 127.9 (2C), 127.4, 114.9, 108.1,
104.9, 102.4, 101.6, 83.2, 76.1 (2C), 71.6, 56.2, 55.9, 48.6,
38.0, 30.3, 26.1; m/z (EI) 468 (Mþ, 2), 273 (15), 268 (12),
262 (41), 91 (100), 87 (23), 59 (24), 43 (16); HRMS (EI)
Mþ; found: 468.1779. C26H28O8 requires: 468.1784.
3.1.8. (E)-4-((2R,3R,5R)-3-(Benzyloxy)tetrahydro-5-
methoxyfuran-2-yl)but-3-en-2-one (19)
To a suspension of silica gel (0.75 g) in dichloromethane
(12.5 mL) previously treated with a 0.65 M aqueous solution
of sodium periodate (1.6 mL, 1.04 mmol) was added a solution
of diol 17 (100 mg, 0.37 mmol) in dichloromethane (3.5 mL).
After 20 min at room temperature the suspension was filtered
and concentrated to give the crude intermediate aldehyde 18
as a pale yellow oil. Then, to a suspension of sodium hydride
(11 mg, 0.44 mmol, 95% dispersion in mineral oil) in THF
(1 mL) was added dropwise at 0 ꢀC a solution of diethyl (2-oxo-
propyl)phosphonate (86 mg, 0.44 mmol) in THF (3 mL). When
the base had dissolved and the evolution of gas had ceased, a so-
lution of crude aldehyde 18 (0.37 mmol) in THF (3 mL) was
added. The cooling bath was removed and the solution was
stirred for 2 h at room temperature, then diluted with diethyl
ether, washed successively with ammonium chloride, brine,
dried over MgSO4, filtered and concentrated in vacuo to give
a pale yellow oil. Purification by flash chromatography eluting
with hexaneseethyl acetate (3:2) gave the title compound as
a colourless oil (61 mg, 60%). [a]2D5 þ26.7 (c 1.3, CH2Cl2);
nmax (film) 2907, 1670, 1631, 1450, 1358, 1251, 1209, 1102,
1028, 978, 943, 737, 695 cmꢁ1; dH (400 MHz, CDCl3) 7.36e
Minor diastereomer (C2 epimer): dH (400 MHz, CDCl3)
7.40e7.22 (5H, m, AreH), 7.07 (1H, d, J 2.3, H-5), 6.63
(1H, d, J 2.3, H-7), 4.93 (1H, dd, J 5.7, 2.4, H-50), 4.45 (1H,
d, J 11.8, OCHAHBPh), 4.16 (1H, d, J 11.8, OCHAHBPh),
4.08e3.88 (3H, m, H-2, H-20 and H-30), 3.93 (3H, s,
AreOMe), 3.90 (3H, s, AreOMe), 3.37 (3H, s, C50-OMe),
2.22 (3H, s, COMe), 2.20e2.03 (2H, m, H2-40).
3.1.10. (R)-4-((2S,3R)-3-(tert-Butyldiphenylsilyloxy)-2,3-
dihydrofuran-2-yl)-2,2-dimethyl-1,3-dioxolane (23)
To a solution of naphthalene (7.12 g, 55.6 mmol) in dry
THF (350 mL) were added at room temperature small pieces
of sodium (4.26 g, 185.2 mmol) previously dipped in methanol
and rinsed with diethyl ether. After 20 min the solution turned
deep green and stirring was continued for 1.5 h. A solution of
compound 11 (5.2 g, 18.7 mmol) in dry THF (50 mL) was

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3921
then added at 0 ꢀC over 5 min. The temperature was then
allowed to warm to room temperature and after 10 min the
mixture was carefully hydrolyzed with water (50 mL) then
poured into diethyl ether (300 mL). After washing with brine,
drying over MgSO4, filtration and concentration in vacuo the
crude alcohol was afforded as a pale yellow oil for use directly
in the next step without further purification. To a solution of
the crude alcohol (18.7 mmol) in dichloromethane (190 mL)
was added at 0 ꢀC imidazole (1.66 g, 24.4 mmol) and
TBDPSCl (6.4 mL, 24.4 mmol). The mixture was allowed to
warm to room temperature and stirred for 16 h. The solution
was poured into water (200 mL) and extracted with dichloro-
methane (3ꢂ100 mL). The combined organic layers were
washed with brine, dried over MgSO4, filtered and concen-
trated in vacuo to give a pale yellow oil. The residue was
purified by flash chromatography eluting with hexaneseethyl
acetate (9:1) to afford the title compound as a colourless oil
(3.25 g, 59% over two steps from 11). [a]2D5 ꢁ53.3 (c 0.92,
CHCl3); nmax (film) 2927, 2855, 1606, 1425, 1367, 1255,
1212, 1147, 1103, 1064, 941, 847, 699 cmꢁ1; dH (400 MHz,
CDCl3) 7.72e7.62 (4H, m, AreH), 7.44e7.38 (6H, m,
AreH), 6.46 (1H, d, J 2.7, H-50), 4.96 (1H, ddd, J 7.0, 2.7,
0.6, H-40), 4.69e4.64 (2H, m, H-4 and H-20), 4.29 (1H, dd,
J 6.8, 5.1, H-30), 4.22 (1H, dd, J 8.4, 6.8, HAHB-5), 4.08
(1H, dd, J 8.4, 6.3, HAHB-5), 1.48 (3H, s, C2-CAH3), 1.39
(3H, s, C2-CBH3), 1.06 (9H, s, OSiMe3); dC (100 MHz,
CDCl3) 149.3, 135.94 (2C), 135.90 (2C), 134.1, 133.2,
129.8, 129.7, 127.7 (2C), 127.5 (2C), 108.7, 104.6, 84.7,
74.2, 73.2, 66.1, 26.9 (3C), 26.5, 25.0, 19.2; m/z (CI, NH3)
425 (MHþ, 1), 309 (22), 241 (21), 216 (20), 199 (31), 169
(22), 128 (30), 111 (69), 101 (100), 94 (36), 78 (57), 72
(19); HRMS (CI) MHþ; found: 425.2151. C25H33O4Si
requires: 425.2148.
CDCl3) 136.1 (2C), 136.0 (2C), 133.6, 132.5, 130.0, 129.9,
127.8 (2C), 127.6 (2C), 110.3, 109.0, 83.5, 78.7, 73.5, 67.4,
55.1, 53.4, 26.8 (3C), 26.7, 25.4, 19.2; m/z (CI, NH3) 554
(MþNHþ4 , 1), 552 (MþNHþ4 , 1), 521 (10), 519 (10), 505 (12),
503 (12), 447 (70), 445 (70), 423 (54), 237 (55), 230 (29), 213
(38), 199 (44), 183 (23), 135 (23), 101 (100), 78 (51); HRMS
(CI) MþNHþ4 ; found: 554.1780, 552.1769. C26H BrNO5Si re-
81
39
79
quires: 554.1760, C26H BrNO5Si requires: 552.1781.
39
3.1.12. (R)-1-((2R,3R,5R)-3-(tert-Butyldiphenylsilyloxy)-5-
methoxytetrahydrofuran-2-yl-1,2-diol (25)
Bromide 24 (1.85 g, 3.45 mmol) was stirred for 16 h at room
temperature in 75% aqueous acetic acid (160 mL) and then for
3 h at 40 ꢀC under reduced pressure (300 mbar). Azeotropic
removal of the acetic acid with toluene under reduced pressure
gave the crude bromo-diol as a colourless oil. The residue was
dissolved in methanol (15 mL), and then treated with triethyl-
amine (0.62 mL, 4.42 mmol) and 10% Pd/C (360 mg,
0.34 mmol). The mixture was stirred vigorously under a hydro-
gen atmosphere (1 atm) for 4 days, then filtered through a pad of
CeliteÒ and concentrated in vacuo. The residue was purified by
flash chromatography eluting with hexaneseethyl acetate (1:1)
to give the title compound as a colourless oil (326 mg, 23%).
nmax (film) 3427, 2987, 2857, 1474, 1419, 1399, 1208, 1009,
950, 719, 694 cmꢁ1 [a]D25 ꢁ37.7 (c 1.1, CHCl3); dH
(400 MHz, CDCl3) 7.72e7.66 (4H, m, AreH), 7.66e7.39
(6H, m, AreH), 4.73 (1H, dd, J 5.6, 4.0, H-5), 4.56 (1H, q,
J 6.9, H-3), 4.24e4.19 (1H, m, H-10), 3.95 (1H, dd, J 9.0, 6.2,
H-2), 3.91e3.87 (1H, m, HAHB-20), 3.81e3.77 (1H, m,
HAHB-20), 3.53 (1H, d, J 2.8, OH), 3.32 (3H, s, C5-OMe),
2.43 (1H, br s, OH), 1.87 (1H, ddd, J 13.8, 7.5, 5.6, HAHB-4),
1.81 (1H, ddd, J 13.8, 6.9, 4.0, HAHB-4), 1.25 (9H, s, SiMe3);
dC (100 MHz, CDCl3) 135.9 (2C), 135.5 (2C), 132.7, 132.1,
130.21, 130.17, 128.0 (2C), 127.8 (2C), 104.5, 78.8, 73.6,
70.7, 64.1, 55.6, 39.5, 26.8 (3C), 19.0; m/z (FABþ, m-nitrobenz-
ylalcohol) 439 (MþNaþ, 12), 416 (Mþ, 40), 387 (11), 223 (23),
203 (47), 199 (60), 197 (57), 137 (57); HRMS (FABþ) Mþ;
found: 416.2007. C23H32O5Si requires: 416.2019.
3.1.11. (R)-4-((2R,3S,4R,5R)-3-(tert-Butyldiphenylsilyloxy)-
4-bromotetrahydro-5-methoxyfuran-2-yl)-2,2-dimethyl-1,3-
dioxolane (24)
To a solution of glycal 23 (1.98 g, 4.66 mmol) and methanol
(1.9 mL, 47.1 mmol) in acetonitrile (20 mL) was added N-bro-
mosuccinimide (880 mg, 4.95 mmol) at 0 ꢀC. The solution
was stirred for 1.5 h at room temperature and the solvent was
evaporated. The residue was dissolved in dichloromethane
(30 mL), washed with saturated sodium thiosulfate and brine,
dried over MgSO4, filtered and concentrated in vacuo to give
a mixture of two diastereomers(84:16). The residuewas purified
by flash chromatography on silica gel eluting with hexanese
ethyl acetate (9:1) to give the title compound as a colourless
oil that solidified on standing (1.23 g, 97%, dr¼82:16). Major
diastereomer: mp 75e80 ꢀC, [a]D25 þ4.3 (c 0.9, CHCl3); nmax
(CHCl3) 2985, 2929, 2855, 1638, 1468, 1425, 1379, 1368,
1205, 1109, 1049, 943, 968 cmꢁ1; dH (400 MHz, CDCl3)
7.76e7.73 (4H, m, AreH), 7.43e7.39 (6H, m, AreH), 5.01
(1H, s, H-5), 4.56 (1H, d, J 4.5, H-3), 4.54 (1H, dt, J 7.2, 6.4,
H-40), 4.38 (1H, dd, J 7.2, 4.5, H-2), 4.20 (1H, dd, J 8.4, 6.4,
HAHB-50), 4.10 (1H, dd, J 8.4, 6.2, HAHB-50), 3.57 (1H, s,
H-4), 3.34 (3H, s, C5-OMe), 1.47 (3H, s, C20-CAH3), 1.38
(3H, s, C20-CBH3), 1.11 (9H, s, OSiMe3); dC (100 MHz,
3.1.13. (E)-4-((2R,3R,5R)-3-(tert-Butyldiphenylsilyloxy)-5-
methoxytetrahydrofuran-2-yl)but-3-en-2-one (27)
To a suspension of silica gel (1.5 g) in dichloromethane
(11 mL) previously treated with sodium periodate (0.65 M,
1.5 mL, 1.0 mmol) was added a solution of diol 25 (310 mg,
0.744 mmol) in dichloromethane (7 mL). After 3 h at room tem-
perature the suspension was filtered and concentrated to give the
crude intermediate aldehyde 26 as a pale yellow oil. Then, to
a suspension of sodium hydride (95%, 23 mg, 0.89 mmol) in
THF (2 mL) was added dropwise at 0 ꢀC a solution of diethyl
(2-oxopropyl)phosphonate (173 mg, 0.89 mmol) in THF
(5 mL). When the base had dissolved and gas evolution had
ceased, a solution of crude aldehyde 26 (0.744 mmol) in THF
(5 mL) was added. The cooling bath was removed and the
solution was stirred for 2.5 h at room temperature and then
diluted with diethyl ether. The organic phase was washed
successively with saturated ammonium chloride and brine, dried
over MgSO4, filtered and concentrated in vacuo to give a pale

3922
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
yellow oil. Purification by flash chromatography eluting with
hexaneseethyl acetate (4:1) gave the title compound as a
colourless oil (230 mg, 73%). [a]2D5 þ15.7 (c 1.0, CHCl3);
nmax 2926, 2857, 1673, 1424, 1361, 1254, 1108, 1032, 976,
737, 702 cmꢁ1; dH (400 MHz, CDCl3) 7.65e7.60 (4H, m,
AreH), 7.44e7.36 (6H, m, AreH), 6.97 (1H, dd, J 16.2, 6.3,
H-4), 6.21 (1H, dd, J 16.2, 1.2, H-3), 4.93 (1H, dd, J 5.7, 3.6,
H-50), 4.50 (1H, dt, J 7.0, 5.9, H-30), 4.40 (1H, dt, J 6.3, 1.2,
H-20), 3.42 (3H, s, C50-OMe), 2.26 (3H, s, COMe), 2.12 (1H,
ddd, J 13.6, 7.0, 5.8, HAHB-40), 1.94 (1H, ddd, J 13.6, 5.6, 3.6,
HAHB-40), 1.05 (9H, s, SiMe3); dC (100 MHz, CDCl3) 198.5,
144.8, 135.8 (2C), 135.7 (2C), 133.3, 133.1, 132.4, 130.0,
129.9, 127.8 (2C), 127.7 (2C), 104.9, 81.3, 73.4, 55.5, 40.5,
26.8 (3C), 26.6, 19.1; m/z (CI, NH3) (MþNHþ4 , 442, 19), 394
(34), 393 (100), 375 (23), 289 (52), 216 (28), 196 (33), 153
(67), 137 (63), 78 (28); HRMS (CI) MþNHþ4 ; found:
442.2398. C25H36NO4Si requires: 442.2414.
solvent was evaporated. The residue was dissolved in dichloro-
methane (50 mL), washed with saturated sodium thiosulfate
and brine, dried over MgSO4, filtered and concentrated invacuo.
The crude residue was purified by flash chromatography eluting
with hexaneseethyl acetate (9:1) to give the title compound as a
colourless oil (3.49 g, 72%, dr¼84:16). Major diastereomer:
[a]2D5 ꢁ45.3 (c 3.1, CH2Cl2); nmax (film) 2926, 2857, 1611,
1510, 1247, 1212, 1170, 1111, 1046, 941, 844,
817, 699 cmꢁ1; dH (300 MHz, CDCl3) 7.72e7.69 (4H, m,
AreH), 7.42e7.25 (8H, m, AreH), 6.88 (2H, d, J 8.7, AreH),
5.20 (1H, s, H-50), 4.67 (1H, d, J 11.3, C50OCHAHBAr),
4.57e4.50 (2H, m, H-30 and H-4), 4.42e4.37 (1H, m, H-20),
4.40 (1H, d, J 11.3, C50OCHAHBAr), 4.17 (1H, dd, J 8.5, 6.4,
HAHB-5), 4.12 (1H, dd, J 8.5, 6.3, HAHB-5), 3.81 (3H, s, Ar-
OMe), 3.67 (1H, s, H-40), 1.46 (3H, s, C2CAH3), 1.36 (3H, s,
C2CBH3), 1.04 (9H, s, SiMe3); dC (75 MHz, CDCl3) 159.3,
136.14 (2C), 130.06 (2C), 133.6, 132.4, 129.9 (2C), 129.6
(2C), 129.5, 127.72 (2C), 127.66 (2C), 113.7 (2C), 109.0,
108.6, 83.7, 78.9, 73.6, 69.7, 67.4, 55.3, 53.9, 26.82 (3C),
26.76, 25.3, 19.3; m/z (EI) 642 (Mþ, 1), 640 (Mþ, 1), 627
3.1.14. 3-Acetyl-2-((2R,3R,5R)-3-(tert-butyldiphenyl-
silyloxy)-5-methoxy-tetrahydrofuran-2-yl)-4-hydroxy-
6,8-dimethoxynaphthalen-1(2H)-one (28)
ꢃ
ꢃ
(Mþ ꢁMe, <1), 625 (Mþ ꢁMe, <1), 199 (5), 149 (3), 122
To a solution of 1,3-dihydro-5,7-dimethoxy-3-oxoisobenzo-
furan-1-carbonitrile 7 (98 mg, 0.446 mmol) and enone 27
(227 mg, 0.534 mmol) in DMSO (20 mL) was added dropwise
a solution of potassium tert-butoxide (65 mg, 0.58 mmol) in
DMSO (10 mL). After 30 min the orange solution was cooled
in an ice bath, diluted with diethyl ether and quenched with sat-
urated ammonium chloride. The mixture was decanted and the
aqueous layer was extracted three times with diethyl ether. The
combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated in vacuo. Purification by flash
chromatography eluting with hexaneseethyl acetate (8:2) gave
the title compound as a yellow oil (182 mg, 66%). [a]2D5 ꢁ35.6
(c 0.9, CHCl3); nmax (film) 2933, 2852, 1784, 1682, 1587,
1455, 1240, 1216, 1160, 1108, 1053, 952, 841, 699 cmꢁ1; dH
(400 MHz, CDCl3) 7.92e7.86 (4H, m, AreH), 7.45e7.35
(6H, m, AreH), 7.22 (1H, d, J 2.3, H-5), 6.57 (1H, d, J 2.3,
H-7), 4.76 (1H, dd, J 6.5, 1.3, H-50), 4.58 (1H, d, J 9.2, H-2),
4.18e4.16 (1H, m, H-30), 3.91 (3H, s, AreOMe), 3.85 (3H, s,
AreOMe), 3.76 (1H, dd, J 9.2, 3.2, H-20), 3.33 (3H, s,
C50-OMe), 2.57 (3H, s, COMe), 1.90e1.85 (1H, m, HAHB-40),
1.70 (1H, ddd, J 14.5, 6.4, 5.2, HAHB-40H), 1.18 (9H, s,
SiMe3); dC (100 MHz, CDCl3) 201.4, 194.5, 167.6, 164.7,
161.1, 138.3, 136.7 (2C), 136.6 (2C), 134.3, 132.6, 129.7,
129.4, 127.5 (2C), 127.2 (2C), 114.8, 108.0, 104.6, 102.4,
101.5, 82.8, 71.4, 56.2, 56.1, 55.8, 48.1, 40.6, 27.2 (3C), 26.4,
19.5; m/z (CI, NH3) 616 (MHþ, 10), 584 (10), 507 (10), 465
(22), 268 (20), 200 (20), 199 (100), 135 (10), 77 (12); HRMS
(CI) Mþ; found: 616.2487. C35H40O8Si requires: 616.2493.
(10), 121 (100), 101 (2). HRMS (EI) Mþ; found: 642.1834,
81
79
640.1866. C33H BrO6Si requires: 642.1835, C33H BrO6Si re-
quires: 640.1856.
41
41
3.1.16. (R)-1-((2R,3R,5R)-3-(tert-Butyldiphenylsilyloxy)-5-
(4-methoxybenzyloxy)tetrahydrofuran-2-yl)-
ethane-1,2-diol (33)
The bromide 32 (2.55 g, 4.00 mmol) was stirred for 7 h at
45 ꢀC under reduced pressure (300 mbar) in 80% aqueous acetic
acid (140 mL). Azeotropic removal of the acetic acid with
toluene under reduced pressure gave the crude bromo-diol as
a colourless oil that was used for the next step without further
purification. To a solution of crude bromo-diol (3.81 mmol) in
dichloromethane (200 mL) was added at ꢁ78 ꢀC tributyltin
hydride (1.54 mL, 5.72 mmol) and triethylborane (1.0 M in
n-hexane, 0.8 mL, 0.76 mmol). Air was then injected into the
solution with a needle (10 mL). The addition of triethylborane
followed with air was repeated every 30 min (three times).
The mixture was then allowed to warm to room temperature
then treated with NaOH (1 M, 60 mL) and vigorously stirred
for 2 h. The mixture was decanted and the aqueous layer
extracted with dichloromethane (3ꢂ). The combined organic
layers were washed with saturated ammonium chloride and
brine, dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography eluting with
hexaneseethyl acetate to give the title compound as a colourless
oil (597 mg, 83% over two steps from 32). [a]2D5 ꢁ88.6 (c 1.4,
CH2Cl2); nmax (film) 3412, 2928, 2853, 1609, 1585, 1510,
1463, 1425, 1300, 1245, 1106, 1031, 817, 701 cmꢁ1; dH
(300 MHz, CDCl3) 7.71e7.65 (4H, m, AreH), 7.68e7.34
(6H, m, AreH), 7.23 (2H, d, J 8.6, AreH), 6.86 (2H, d, J 8.6,
AreH), 4.94 (1H, dd, J 5.6, 3.9, H-50), 4.67 (1H, d, J 11.3,
OCHAHBAr), 4.56 (1H, q, J 6.7, H-30), 4.35 (1H, d, J 11.3,
OCHAHBAr), 4.31e4.24 (1H, m, H-1), 3.98 (1H, dd, J 9.0,
6.1, H-20), 3.96e3.76 (2H, m, CH2), 3.78 (3H, s, ArOMe),
3.48 (1H, d, J 2.8, OH), 2.40e2.30 (1H, m, OH), 1.93 (1H,
3.1.15. (R)-4-((2R,3S,4R,5R)-4-Bromo-3-(tert-butyldiphen-
ylsilyloxy)-5-(4-methoxybenzyloxy)tetrahydrofuran-2-yl)-
2,2-dimethyl-1,3-dioxolane (32)
To a solution of glycal 23 (3.19 g, 7.51 mmol) and p-meth-
oxybenzyl alcohol (5.2 g, 37.6 mmol) in acetonitrile (32 mL)
was added N-bromosuccinimide (1.40 g, 7.89 mmol) at 0 ꢀC.
The solution was stirred for 1.5 h at room temperature and the

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3923
ddd, J 13.9, 6.5, 4.0, HAHB-40), 1.86 (1H, ddd, J 13.9, 7.5, 5.9,
HAHB-40), 1.07 (9H, s, SiMe3); dC (75 MHz, CDCl3) 159.2,
136.0 (2C), 135.6 (2C), 132.7, 132.1, 130.1 (2C), 129.5 (2C),
128.0 (2C), 127.8 (2C), 113.7 (2C), 102.4, 79.2, 73.7, 70.7,
69.7, 64.2, 55.2, 39.6, 26.9 (3C), 19.0; m/z (FABþ, m-nitrobenz-
ylalcohol) 545 (MþNaþ, <1), 203 (4), 199 (8), 197 (8), 122
(100), 121 (100), 91 (4). HRMS (FABþ), MþNaþ, found:
545.2342. C30H38NaO6Si requires: 545.2335.
the aqueous layer extracted three times with diethyl ether. The
combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated in vacuo to give a yellow
oil. Purification by flash chromatography eluting with
hexaneseethyl acetate (8:2) gave the title compound as a yellow
solid (96 mg, 53%). [a]2D5 ꢁ13.3 (c 1.3, CH2Cl2); nmax (CHCl3)
3390, 2929, 2851, 1787, 1680, 1585, 1510, 1457, 1425, 1336,
1241, 1212, 1159, 1106, 1035, 950, 819, 702 cmꢁ1; dH
(400 MHz, CDCl3) 7.92 (2H, dd, J 7.7, 1.9, AreH), 7.85 (2H,
dd, J 8.0, 1.2, AreH), 7.45e7.17 (9H, m, AreH), 6.90e6.88
(2H, m, AreH), 6.57 (1H, d, J 2.3, H-70), 4.98 (1H, d, J 5.7,
H-50), 4.70 (1H, d, J 11.3, OCHAHBAr), 4.62 (1H, d, J 9.5,
H-C2), 4.32 (1H, d, J 11.3, OCHAHBAr), 4.14 (1H, t, J 3.8,
H-30), 3.92 (3H, s, OCH2Ar), 3.85e3.83 (6H, 2s, C6-OMe and
C8-OMe), 3.76 (1H, dd, J 9.5, 3.1, H-20), 2.59 (3H, s, COMe),
1.98 (1H, d, J 14.5, HAHB-C40), 1.73 (1H, ddd, J 14.5, 6.7,
5.2, HAHB-40), 1.16 (9H, s, SiMe3); dC (100 MHz, CDCl3)
201.6, 194.5, 167.5, 164.7, 161.1, 159.1, 138.2, 136.7 (2C),
136.6 (2C), 134.3, 132.4, 130.0, 129.7, 129.3 (3C), 127.6
(2C), 127.0 (2C), 114.8, 113.7 (2C), 108.1, 102.8, 102.4,
101.5, 83.1, 71.3, 70.4, 56.2, 55.8, 55.3, 48.2, 40.7, 27.2 (3C),
3.1.17. (E)-4-((2R,3R,5R)-5-(4-Methoxybenzyloxy)-3-(tert-
butyldiphenylsilyloxy)tetrahydrofuran-2-yl)but-
3-en-2-one (35)
To a suspension of silica gel (2.3 g) in dichloromethane
(18 mL) previously treated with sodium periodate (0.65 M,
2.3 mL, 1.5 mmol) was added a solution of diol 33 (597 mg,
1.14 mmol) in dichloromethane (10 mL). After 5 h at room tem-
perature the suspension was filtered and concentrated to give the
crude intermediate aldehyde 34 as a pale yellow oil. Then, to
a suspension of sodium hydride (95%, 35 mg, 1.37 mmol) in
THF (3 mL) was added dropwise at 0 ꢀC a solution of diethyl
(2-oxopropyl)phosphonate (266 mg, 1.37 mmol) in THF
(8 mL). When all the base had dissolved and the evolution of
gas had ceased, a solution of crude aldehyde 34 (1.14 mmol)
in THF (8 mL) was added. The solution was stirred for 30 min
at 0 ꢀC and then diluted with diethyl ether. The organic phase
was washed successively with saturated ammonium chloride
and brine, dried over MgSO4, filtered and concentrated invacuo.
Purification by flash chromatography on silica gel eluting with
hexaneseethyl acetate (8:2) gave the title compound as a colour-
less oil (482 mg, 80%). [a]2D5 ꢁ4.6 (c 1.1, CH2Cl2); nmax (film)
2929, 2851, 1677, 1609, 1514, 1425, 1358, 1248, 1109, 1024,
702 cmꢁ1; dH (400 MHz, CDCl3) 7.64e7.59 (4H, m, AreH),
7.44e7.25 (8H, m, AreH), 6.99 (1H, dd, J 16.2, 6.4, H-4),
6.88 (2H, d, J 8.6, AreH), 6.22 (1H, dd, J 16.2, 1.0, H-3),
5.13 (1H, dd, J 5.6, 3.4, H-50), 4.78 (1H, d, J 11.3, OCHAHBAr),
4.49 (1H, br s, J 6.2, H-30), 4.45 (1H, d, J 11.3, OCHAHBAr),
4.42 (1H, dt, J 6.3, 1.0, H-20), 3.80 (3H, s, ArOMe), 2.21 (3H,
s, H3-C1), 2.17e2.10 (1H, m, HAHB-C40), 2.04 (1H, ddd,
J 13.7, 5.4, 3.4, HAHB-C40), 1.03 (9H, s, SiMe3); dC
(100 MHz, CDCl3) 198.5, 159.2, 144.8, 135.8 (2C), 135.7
(2C), 133.3, 133.0, 132.4, 130.0, 129.90, 129.86, 129.5 (2C),
127.8 (2C), 127.7 (2C), 113.7 (2C), 102.8, 81.6, 73.4, 69.5,
55.3, 40.7, 26.7 (3C), 26.6, 19.1; m/z (CI, NH3) 548 (MþNHþ4 ,
<1), 216 (10), 199 (10), 196 (12), 139 (14), 137 (26), 122 (15),
121 (100), 78 (14); HRMS (CI) MþNHþ4 ; found: 548.2824.
C32H42NO5Si requires: 548.2832.
ꢃ
26.6, 19.5; m/z (FABþ, m-nitrobenzylalcohol) 722 (Mþ , <1),
585 (2), 383 (9), 262 (5), 197 (4), 122 (11), 121 (100); HRMS
(FABþ) Mþ; found: 722.2903. C42H46O9Si requires: 722.2911.
3.1.19. (E)-4-((2R,3R)-3-(tert-Butyldiphenylsilyloxy)-5-
hydroxy-tetrahydrofuran-2-yl)but-3-en-2-one (38)
To a solution of 35 (25 mg, 0.05 mmol) in a mixture of di-
chloromethane (1 mL) and phosphate buffer (pH 7.4, 0.05 mL)
was added DDQ (18 mg, 0.08 mmol). After stirring vigorously
at room temperature for 2 h, the mixture was hydrolyzed with
saturated sodium bicarbonate and extracted with dichlorome-
thane (3ꢂ5 mL). The combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated in
vacuo. Purification by flash chromatography eluting with
hexaneseethyl acetate (3:2) gave the title compound as a col-
ourless oil (15 mg, 78%), and as a mixture of two anomers
(anti/syn, 56:44). nmax (film) 3407, 2926, 2857, 1673, 1632,
1427, 1358, 1254, 1108, 1039, 976, 820, 740, 702 cmꢁ1; m/z
(CI, NH3) (MþNHþ4 , 4), 393 (10), 274 (31), 216 (71), 199
(62), 198 (23), 196 (100), 155 (23), 139 (59), 137 (84), 94
(26), 78 (51); HRMS (CI) MþNHþ4 ; found: 428.2242.
C24H34NO4Si requires: 428.2257.
anti: dH (400 MHz, CDCl3) 7.62e7.60 (4H, m, AreH),
7.44e7.38 (6H, m, AreH), 6.78 (1H, dd, J 11.6, 5.7, H-4),
6.22 (1H, dd, J 16.1, 1.4, H-3), 5.68 (1H, dt, J 5.4, 3.1, H-50),
4.70 (1H, dt, J 6.0, 4.7, H-30), 4.62 (1H, dt, J 5.4, 1.4, H-20),
2.83 (1H, d, J 3.2, OH), 2.20 (3H, s, C1), 2.16e2.09 (1H, m,
HAHB-C40), 1.93 (1H, ddd, J 13.8, 6.0, 2.8, HAHB-C40), 1.05
(9H, s, SiMe3); dC (100 MHz, CDCl3) 198.2, 143.3, 135.71
(2C), 135.69 (2C), 133.3, 132.9, 131.8, 130.02, 130.00,
127.83 (2C), 127.77 (2C), 97.9, 80.5, 74.7, 43.0, 26.8 (3C),
26.7, 19.1.
3.1.18. 3-Acetyl-2-((2R,3R,5R)-3-(tert-butyldiphenyl-
silyloxy)-5-(4-methoxybenzyloxy)tetrahydrofuran-2-yl)-4-
hydroxy-6,8-dimethoxynaphthalen-1(2H)-one (36)
To a solution of 1,3-dihydro-5,7-dimethoxy-3-oxoisobenzo-
furan-1-carbonitrile 7 (54 mg, 0.25 mmol) and enone 35
(158 mg, 0.30 mmol) in DMSO (10 mL) was added dropwise
a solution of potassium tert-butoxide (35 mg, 0.30 mmol) in
DMSO (5 mL). After 30 min the orange solution was cooled
in an ice bath, diluted with diethyl ether and quenched with
saturated ammonium chloride. The mixture was decanted and
syn: [a]2D5 þ66.7 (c 1.2, CH2Cl2); dH (400 MHz, CDCl3)
7.62e7.60 (4H, m, AreH), 7.44e7.38 (6H, m, AreH), 6.72
(1H, dd, J 5.8, 16.0, H-40), 6.32 (1H, dd, J 16.0, 1.4, H-3),
5.43 (1H, dd, J 11.5, 4.8, H-50), 4.54 (1H, dt, J 4.1, 1.5,

3924
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
H-30), 4.37 (1H, ddd, J 5.8, 3.9, 1.4, H-20), 3.87 (1H, d, J 11.5,
C50OH), 2.15 (3H, s, H3-C1), 2.11 (1H, d, J 13.8, HAHB-40),
2.01 (1H, dt, J 13.8, 4.6, HAHB-40), 1.07 (9H, s, SiMe3); dC
(100 MHz, CDCl3) 197.9, 143.2, 135.9 (2C), 135.8 (2C),
132.3, 132.04, 131.98, 130.33, 130.31, 128.0 (4C), 99.5,
83.4, 74.7, 42.6, 27.2, 26.9 (3C), 19.1.
HAHB-C3), 2.18 (1H, dd, J 17.3, 4.2, HAHB-C3), 1.18 (9H, s,
SiMe3); dC (100 MHz, CDCl3) 195.5, 192.4, 173.7, 170.2,
165.2, 161.1, 138.1, 136.4 (2C), 135.8, 135.7 (2C), 133.5,
131.4, 130.2, 130.0, 127.9 (2C), 127.8 (2C), 106.3, 102.8,
101.9, 84.3, 70.7, 56.3, 55.9, 47.7, 39.4, 27.0 (3C), 25.2, 19.5;
m/z (EI) 566 (23), 480 (24), 479 (64), 465 (12), 300 (19), 200
(19), 199 (100), 134 (38), 69 (41), 57 (64), 55 (62), 43 (64),
41 (64); HRMS (EI) MHþ; found: 601.2254. C34H37O8Si
requires: 601.2258.
3.1.20. (4R,5R,10E)-4-(tert-Butyldiphenylsilyloxy)-5-(3-
oxobut-1-enyl)dihydrofuran-2(3H)-one (39)
PCC (1.52 g, 7.04 mmol), anhydrous sodium acetate
˚
(577 mg, 7.04 mmol), 4 A MS (1.8 g) and anhydrous dichloro-
3.1.22. 2-Acetyl-3-((2R,3R)-3-(tert-butyldiphenylsilyloxy)-5-
oxo-tetrahydrofuran-2-yl)-4-hydroxy-5,7-dimethoxy-
naphthalen-1-yl acetate (41)
methane (14 mL) were placed in a light protected flask and
stirred under a nitrogen atmosphere for 10 min. A solution
of lactol 38 (688 mg, 1.68 mmol) in dichloromethane (8 mL)
was added. After 2 h at room temperature the mixture was
diluted with diethyl ether (50 mL) and filtered through a Flori-
silÒ pad to give the title compound as a colourless oil (620 mg,
91%). [a]2D5 þ49.7 (c 3.5, CH2Cl2); nmax (film) 2954, 2926,
2857, 1788, 1677, 1639, 1424, 1358, 1257, 1150, 1105,
1025, 980, 948, 820, 740, 702 cmꢁ1; dH (400 MHz, CDCl3)
7.60e7.57 (4H, m, AreH), 7.48e7.37 (6H, m, AreH), 6.79
(1H, dd, J 16.1, 5.7, H-10), 6.33 (1H, dd, J 16.1, 1.3, H-20),
4.88 (1H, dt, J 5.1, 1.3, H-5), 4.66 (1H, dt, J 5.0, 3.4, H-4),
2.52 (1H, dd, J 17.4, 5.3, HAHB-C3), 2.46 (1H, dd, J 17.4,
3.3, HAHB-C3), 2.31 (3H, s, C40), 1.05 (9H, s, SiMe3); dC
(100 MHz, CDCl3) 197.1, 174.0, 138.9, 135.6 (4C), 132.5,
132.3, 132.0, 130.4 (2C), 128.0 (4C), 82.5, 71.2, 38.3, 27.4,
26.7 (3C), 19.1; m/z (CI, NH3) 426 (MþNHþ4 , 6), 309 (9),
216 (23), 199 (65), 110 (23), 109 (23), 108 (20), 94 (60), 93
(35), 78 (100); HRMS (CI) MþNHþ4 ; found: 426.2103.
C24H32NO4Si requires: 426.2101.
To a solution of crude 40 (0.734 mmol) in dichloromethane
(15 mL) was added at ꢁ78 ꢀC boron trifluoride diethyl ether-
ate (186 mL, 1.47 mmol). The temperature was raised to
ꢁ10 ꢀC over 20 min, then after 10 min at this temperature
pyridine (6 mL) and acetic anhydride (4 mL) were added
and the mixture was stirred at room temperature for 5 h. The
reaction was quenched with water and extracted with dichloro-
methane (3ꢂ30 mL). The combined organic layers were
washed with water, brine, dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash chromatography
eluting with hexaneseethyl acetate (7:3) gave the title com-
pound as a yellow oil (250 mg, 53%). Major diastereomer:
[a]2D5 þ46.2 (c 2.1, CH2Cl2); nmax (film) 3358, 2940, 2857,
1777, 1701, 1628, 1587, 1469, 1424, 1368, 1195, 1170,
1146, 1108, 1042, 1007, 907, 820, 733, 702 cmꢁ1; dH
(400 MHz, CDCl3) 9.41 (1H, s, C4-OH), 7.59e7.10 (10H,
m, AreH), 6.51 (1H, d, J 2.2, AreH), 6.48 (1H, d, J 2.2,
AreH), 5.63 (1H, d, J 4.2, H-20), 4.95 (1H, dt, J 7.2, 4.9,
H-30), 4.00 (3H, s, C5-OMe), 3.89 (3H, s, C7-OMe), 2.72
(1H, dd, J 17.9, 7.7, HAHB-C40), 2.52 (3H, s, C2-COMe),
2.47 (1H, dd, J 17.9, 5.0, HAHB-C40), 2.36 (3H, s, OCOMe),
1.05 (9H, s, SiMe3); dC (100 MHz, CDCl3) 203.3, 175.4,
168.9, 159.4, 157.5, 151.4, 135.7 (4C), 133.6, 133.5,
133.4, 132.4, 130.4, 129.8, 129.5, 127.7 (2C), 127.4 (2C),
111.4, 110.8, 99.2, 93.3, 84.4, 73.8, 56.5, 55.4, 38.8,
32.4, 26.8 (3C), 20.6, 14.2; m/z (FABþ, m-nitrobenzylalcohol)
643 (MHþ, 20), 273 (12), 120 (12), 89 (22); HRMS
(FABþ) MHþ; found: 643.2358. C36H39O9Si requires:
643.2363.
3.1.21. (4R,5R)-5-(3-Acetyl-4-hydroxy-6,8-dimethoxy-1-
oxo-1,2-dihydronaphthalen-2-yl)-4-(tert-butyldiphenyl-
silyloxy)dihydrofuran-2(3H)-one (40)
To
a solution of potassium tert-butoxide (104 mg,
0.88 mmol) in DMSO (8 mL) was added at room temperature
a solution of 1,3-dihydro-5,7-dimethoxy-3-oxoisobenzofuran-
1-carbonitrile 7 (193 mg, 0.88 mmol) in DMSO (11 mL)
followed by a solution of enone 39 (300 mg, 0.734 mmol) in
DMSO (11 mL). After 10 min the orange solution was cooled
in an ice bath, diluted with diethyl ether and quenched with
saturated ammonium chloride. The mixture was decanted and
the aqueous layer was extracted three times with diethyl ether.
The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated in vacuo to give the title
compound as a yellow solid (440 mg, 81%), which was used for
the next step without further purification. A sample was purified
for analytical purposes by flash chromatography eluting with
hexaneseethyl acetate (7:3). [a]2D5 þ15.4 (c 2.0, CH2Cl2);
nmax (CHCl3) 3372, 2926, 2857, 1791, 1684, 1587, 1455,
1323, 1243, 1139, 1107, 1035, 948, 737, 702 cmꢁ1; dH
(400 MHz, CDCl3) 7.92e7.87 (2H, m, AreH), 7.70e7.66
(2H, m, AreH), 7.48e7.41 (6H, m, AreH), 7.25 (1H, d, J 2.4,
H-50), 6.60 (1H, d, J 2.4, H-70), 4.62 (1H, d, J 10.4, H-20), 4.39
(1H, t, J 3.3, H-4), 4.25 (1H, dd, J 10.4, 2.7, H-5), 3.93, 3.88
(6H, s, 2 ArOMe), 2.44 (3H, s, COMe), 2.36 (1H, d, J 17.3,
3.1.23. 2-Acetyl-3-((2R,3R)-3-hydroxy-5-oxotetrahydro-
furan-2-yl)-5,7-dimethoxynaphthalene-1,4-dione (44)
To a solution of 41 (64 mg, 0.093 mmol) in THF (6 mL)
placed in a polypropylene flask was added HF$Py (1.5 mL).
After stirring at room temperature for 6 h the solution was
poured carefully into saturated sodium bicarbonate. The mix-
ture was decanted and the organic layer was extracted with di-
chloromethane (3ꢂ10 mL). The combined organic layers were
washed with brine, dried over MgSO4, filtered and concen-
trated in vacuo to give a mixture of 42 and 43 (4:1) (60 mg),
which was used without further purification for the next
step. A sample was purified by flash chromatography on silica
gel eluting with ethyl acetateehexanes (1:1/2:3) to give
a mixture of 42 and 43 (1:4).

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3925
To a solution of a mixture of 42 and 43 (4:1, 150 mg,
0.4 mmol) in acetonitrile (20 mL) was added at room tempera-
ture a solution of ceric ammonium nitrate (640 mg, 1.17 mmol)
in water (10 mL). After stirring for 15 min the solution was
quenched with saturated sodium bicarbonate and extracted three
times with dichloromethane. The combined organic layers were
washed with brine, dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash chromatography eluting with
hexaneseethyl acetate (1:1/1:1þ1% MeOH) gave the title
compound as a yellow oil (44 mg, 38% over two steps starting
from 41). nmax (film) 3289, 2909, 1731, 1689, 1599, 1478,
1499, 1375, 1312, 1274, 1251, 1190, 1100, 747 cmꢁ1; dH
(400 MHz, CDCl3) 7.20 (1H, d, J 2.4, H-8), 6.75 (1H, d, J 2.4,
H-6), 5.40 (1H, d, J 3.6, H-20), 4.58 (1H, dt, J 8.1, 4.0, H-30),
3.99 (3H, s, ArOMe), 3.97 (3H, s, ArOMe), 3.02 (1H, dd, J
18.4, 8.3, HAHB-C40), 2.61 (1H, dd, J 18.4, 4.2, HAHB-C40),
2.51 (3H, s, C2-COMe); dC (100 MHz, CDCl3) 201.9, 183.3,
183.2, 173.8, 169.9, 162.3, 142.4, 135.8, 134.9, 113.2, 104.5,
104.0, 83.9, 72.3, 56.6, 56.2, 35.7, 31.7;m/z (FABþ, m-nitrobenz-
ylalcohol) 361 (MHþ, 1), 273 (3), 219 (4), 124 (10), 120 (13), 91
(18), 90 (20), 89 (29); HRMS (FABþ) MHþ; found: 361.0865.
C18H17O8 requires: 361.0923.
2843, 1736, 1649, 1590, 1562, 1455, 1431, 1323, 1271, 1250,
1198, 1153, 1105, 1063 cmꢁ1; dH (400 MHz, CDCl3) 7.21
(1H, d, J 2.4, H-90), 6.71 (1H, d, J 2.4, H-70), 4.85e4.78 (1H,
m, H-10), 3.97 (3H, s, ArOMe), 3.95 (3H, s, ArOMe),
3.97e3.89 (1H, m, H-30), 3.73 (3H, s, CO2Me), 2.86 (1H, dt,
J 18.8, 2.6, HAHB-C40), 2.71 (1H, dd, J 15.7, 7.8, HAHB-C2),
2.62 (1H, dd, J 15.7, 5.2, HAHB-C2), 2.26 (1H, ddd, J 18.6,
10.5, 3.8, HAHB-C40), 1.50 (3H, d, J 6.8, C10-Me); dC
(100 MHz, CDCl3) 183.8, 181.6, 171.2, 164.6, 161.7, 143.9,
143.7, 136.3, 114.0, 103.9, 103.0, 69.9, 69.4, 56.4, 55.9, 51.8,
40.4, 28.4, 20.5; m/z (FABþ, m-nitrobenzylalcohol) 361
(MHþ, 40), 360 (Mþ, 17), 149 (12), 120 (12); HRMS (FABþ)
MHþ; found: 361.1287. C19H21O7 requires: 361.1287.
3.1.26. N,N-Diethyl 3,5-dimethoxybenzamide (48)18
3,5-Methoxybenzoic acid (12.0 g, 65.7 mmol) was taken up
in dichloromethane (100 mL) and cooled to ꢁ10 ꢀC. Thionyl
chloride (5.3 cm3, 72.3 mmol) was added dropwise and the
reaction mixture stirred at room temperature for 16 h. The reac-
tion mixture was concentrated in vacuo with azeotropic removal
of the residual thionyl chloride with toluene (2ꢂ50 mL). The
resulting crude acid chloride was taken up in dichloromethane
(100 mL) and cooled to 0 ꢀC. A solution of diethylamine
(20 mL) in dichloromethane (20 mL) was added dropwise, the
reaction mixture warmed to room temperature and stirred for
2 h. Glacial acetic acid (30 mL) was added and the reaction
mixture was diluted with dichloromethane (100 mL), washed
with water (100 mL), brine (100 mL), dried (MgSO4), filtered
and concentrated invacuo. Purification byflash chromatography
eluting with hexaneseethyl acetate (2:1) gave the title com-
pound (10.4 g, 46.6 mmol, 71%) as a yellow oil. nmax (film)
2945, 1680 cmꢁ1; dH (300 MHz, CDCl3) 6.45 (2H, d, J 2.2,
AreH), 6.40 (1H, t, J 2.2, AreH), 3.81 (6H, s, 2ꢂOMe),
3.52e3.39 (2H, br m, CH2), 3.27e3.20 (2H, br m, CH2),
1.24e1.10 (3H, br m, Me), 1.12e1.06 (3H, br m, Me). Spectro-
scopic data consistent with the literature.18
3.1.24. 2-((1S,3S)-6,8-Dimethoxy-1-methyl-5,10-dioxo-
3,4,5,10-tetrahydro-1H-benzo[g]isochromen-3-yl)-
acetic acid (46)
To a solution of quinone 44 (38 mg, 0.105 mmol) in dichloro-
methane (5 mL) was added at ꢁ78 ꢀC boron trifluoride diethyl
etherate (134 mL, 1.05 mmol) followed by triethylsilane
(168 mL, 1.05 mmol). The solution was stirred at ꢁ78 ꢀC for
15 min then allowed to warm to room temperature over 30 min.
The dark red mixturewas then concentrated invacuo and purified
by flash chromatography eluting with hexaneseethyl acetatee
methanol (10:10:1) to afford the title compound as a red-orange
solid (23 mg, 63%). nmax (CH2Cl2) 2923, 1720, 1647, 1593,
1454, 1424, 1349, 1325, 1274, 1250, 1198, 1159 cmꢁ1; dH
(300 MHz, CDCl3) 7.21 (1H, d, J 2.4, H-90), 6.73 (1H, d, J 2.4,
H-70), 4.89e4.80 (1H, m, H-10), 3.96 (3H, s, ArOMe), 3.95
(3H, s, ArOMe), 3.96e3.84 (1H, m, H-30), 2.91 (1H, dt, J 18.6,
2.6, HAHB-C40), 2.76 (1H, dd, J 16.0, 7.4, HAHB-C2), 2.69
(1H, dd, J 16.0, 5.4, HAHB-C2), 2.25 (1H, ddd, J 18.6, 10.5,
3.7, HAHB-C40), 1.52 (3H, d, J 6.6, C10-Me); dC (75 MHz,
CDCl3) 183.7, 181.5, 174.4, 164.7, 161.8, 143.7, 143.5, 136.3,
114.1, 104.0, 103.1, 70.0, 69.2, 56.4, 55.9, 40.1, 28.4, 20.5; m/z
(FABþ, glycerol) 347 (MHþ, 1), 75 (29); HRMS (FABþ)
MHþ; found: 347.1123. C18H19O7 requires: 347.1131.
3.1.27. N,N-Diethyl 3-hydroxy-5-methoxybenzamide (49)
N,N-Diethyl
3,5-dimethoxybenzamide
48
(3.01 g,
12.7 mmol) was dissolved in dichloromethane (250 mL). The
solution was cooled to ꢁ78 ꢀC, boron tribromide (20 mL,
20 mmol) was added dropwise and the reaction mixture stirred
for 1 h. The reaction was quenched by the addition of HCl
(1 M, 50 mL). The aqueous layer was extracted with dichloro-
methane (2ꢂ50 mL) and the combined organic extracts were
washed with brine, dried with MgSO4, concentrated and purified
by flash column chromatography (hexaneeethyl acetate 1:1) to
give the title compound as white crystals (2.10 g, 9.42 mmol,
72%), mp 103e105 ꢀC. nmax (CH2Cl2) 3414, 2977, 1635,
1428, 1381, 1364, 1258, 1159, 1119 cmꢁ1; dH (400 MHz,
CDCl3) 8.29 (1H, s, OH), 6.36e6.33 (1H, m, AreH),
6.45e6.36 (1H, m, AreH), 6.34e6.32 (1H, m, H-4), 3.71
(3H, s, OMe), 3.57e3.46 (2H, q, J 6.7, CH2), 3.32e3.20 (2H,
q, J 6.7, CH2), 1.26e1.19 (3H, t, J 6.7, Me), 1.14e1.05 (3H, t,
J 6.7, Me); dC (100 MHz, CDCl3) 172.4, 161.1, 158.8, 138.1,
107.1, 103.8, 103.1, 55.7, 43.9, 39.6, 14.6, 13.2; HRMS (EI)
Mþ; found: 223.1210; C12H17NO3 requires: 223.1208.
3.1.25. Methyl 2-((1S,3S)-6,8-dimethoxy-1-methyl-5,10-
dioxo-3,4,5,10-tetrahydro-1H-benzo[g]isochromen-3-yl)-
acetate (47)
A solution of quinone 46 (21 mg, 0.061 mmol) in methanol
(20 mL) protected from light was stirred for 6 weeks and oxygen
was bubbled daily through the solution. The solvent was then
removed in vacuo and the crude mixture purified by flash chro-
matography eluting with hexaneseethyl acetateemethanol
(20:20:1) to afford the title compound as a red-orange oil
(7 mg, 32%). [a]D20 ꢁ206 (c 0.7, CH2Cl2); nmax (film) 2933,

3926
O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
3.1.28. 3-Diethylcarbamoyl-5-methoxyphenyl trifluoro-
methanesulfonate (50)
was poured into 1 M HCl (200 mL). The aqueous phase was
extracted with ethyl acetate (5ꢂ50 mL). The combined organic
phase was extracted with sodium bicarbonate (2ꢂ50 mL), brine,
dried (MgSO4) and concentrated to afford light brown crystals.
Recrystallization from ethyl acetate gave the title compound as
white crystals (1.62 g, 3.69 mmol, 92%), mp 248e250 ꢀC.
nmax (CH2Cl2) 3468, 2991, 2912, 2878, 2245, 1696, 1651,
1599, 1419, 1280 cmꢁ1; dH (300 MHz, CDCl3) 10.51 (2H, s,
CHO and C0HO), 7.15 (2H, d, J 1.2, H-2 and H-20), 7.04 (2H,
d, J 1.2, H-6 and H0-6), 4.02 (6H, s, 2ꢂOMe), 3.61 (4H, br q,
J 7.2, 2ꢂCH2), 3.11 (4H, q, J 7.2, 2ꢂCH2), 1.35 (6H, t, J 7.2,
2ꢂMe), 1.03 (6H, t, J 7.2, 2ꢂMe); dC (75 MHz, CDCl3) 188.7
(2C), 169.3 (2C), 162.5 (2C), 146.7 (2C), 140.2 (2C), 121.1
(2C), 118.2 (2C), 110.6 (2C), 56.3 (2C), 42.6 (2C), 38.8 (2C),
13.6 (2C), 12.1 (2C); HRMS (EI) MHþ; found: 439.2327.
C26H33N2O6 requires: 439.2339.
N,N-Diethyl 3-hydroxy-5-methoxybenzamide 49 (3.12 g,
14.0 mmol) and N-phenyltrifluoromethanesulfonimide (5.09 g,
14.2 mmol) was dissolved in dichloromethane (150 mL) and
cooled to ꢁ20 ꢀC. Triethylamine was added and the reaction
was allowed to warm to room temperature. After 3 h the reaction
was complete as determined by TLC analysis and the mixturewas
washed with saturated ammonium chloride, dried over MgSO4,
filteredandconcentrated.Purificationbyflashcolumnchromatog-
raphy (hexaneseethyl acetate 4:1 to 1:1) gave the title compound
(4.01 g, 11.3 mmol, 80%) as a light yellow oil. nmax (film) 3486,
2976, 1736, 1634, 1426, 1326, 1213, 1141, 1053, 961, 833, 802,
761 cmꢁ1; dH (300 MHz, CDCl3) 6.94 (1H, dd, J 1.7, 1.3,
AreH), 6.86 (1H, dd, J 1.3, 0.9 AreH), 6.83e6.80 (1H, m,
AreH), 3.85 (3H, s, OMe), 3.63e3.43 (2H, br m, CH2), 3.35e
3.15 (2H, br m, CH2), 1.30e1.16 (6H, br m, 2ꢂMe); dC
(75 MHz, CDCl3) 168.7, 161.0, 149.8, 140.0, 112.1, 111.3,
108.4, 55.9, 43.3, 39.6, 14.1, 12.9, triflate carbon not observed;
HRMS (EI) Mþ; found: 355.0702. C13H16F3NO5S requires:
355.0701.
3.1.31. 7,70-Dimethoxy-3,30-dioxo-1,3,10,30-tetrahydro-
[5,50]biisobenzofuranyl-1,10-dicarbonitrile (4)
A solution of 52 (62 mg, 0.12 mmol) in dichloromethane
(10 mL) was cooled to 0 ꢀC. Trimethylsilyl cyanide (48 mL,
0.36 mmol), potassium cyanide (1.6 mg, 1.6 mmol) and 18-
crown-6 (2 mg) were added and the reaction mixture was stirred
for 2 h. The reaction mixture was concentrated in vacuo and the
resulting residue taken up in glacial acetic acid (5 mL) then
stirred at room temperature for 16 h. The resulting mixture
was partitioned between ethyl acetate (25 mL) and sodium hy-
droxide solution (1 M, 25 mL) then the aqueous layer was ex-
tracted with ethyl acetate (3ꢂ10 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated invacuo.
Purification by flash chromatography eluting with hexanese
ethyl acetate (1:4) gave the title compound (37 mg, 82%). nmax
(CH2Cl2) 3555, 2989, 2941, 2912, 1741, 1449, 1363, 1241,
747 cmꢁ1; dH (300 MHz, d6-DMSO) 8.00 (2H, br s, H-4 and
H-40), 7.86 (2H, br s, H-6 and H0-6), 6.89 (2H, s, CHCN), 4.13
(6H, s, 2ꢂOMe); dC (75 MHz, d6-DMSO) 167.4, 154.3, 144.2,
129.2, 126.2, 117.1, 116.3, 114.0, 64.4, 56.8; HRMS (EI)
MHþ; found: 377.0775. C20H13N2O6 requires: 377.0773.
3.1.29. 5,50-Dimethoxy-biphenyl-3,30-dicarboxylic acid
bisdiethylamide (51)
3-Diethylcarbamoyl-5-methoxyphenyltrifluoromethane sul-
fonate 50 (3.98 g, 11.2 mmol), bis(pinacolatodiboron) (1.39 g,
5.53 mmol), potassium carbonate (4.94 g, 36.2 mmol), 1,10-
bis(diphenylphosphino)-ferrocene (295 mg, 0.54 mmol) and
[1,10-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)
(5 mol %, 435 mg, 0.54 mmol) were dissolved in dioxane
(120 mL) and heated to reflux for 3 h. The mixture was cooled
to room temperature and diluted with ethyl acetate (100 mL).
The mixture was washed with water (2ꢂ100 mL) and the
water was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried (MgSO4) and concen-
trated. Further purification by flash column chromatography
(hexaneeethyl acetate 1:1) gave the title compound as white
crystals (2.08 g, 5.05 mmol, 90%), mp 125e127 ꢀC. nmax
(film) 3054, 2986, 1772, 1626, 1422, 1265, 736 cmꢁ1; dH
(400 MHz, CDCl3) 7.14e7.12 (4H, m, H-2, H-20, H-4 and
H-40), 6.89 (2H, dd, J 3.5 and 1.4, H-6 and H-60), 3.87 (6H,
s, 2ꢂOMe), 3.64e3.46 (4H, br m, 2ꢂCH2), 3.39e3.21 (4H,
br m, 2ꢂCH2), 1.31e1.19 (6H, br m, 2ꢂMe), 1.18e1.06
(6H, br m, 2ꢂMe); dC (100 MHz, CDCl3) 171.2 (2C), 160.4
(2C), 142.6 (2C), 139.5 (2C), 117.8 (2C), 114.2 (2C), 111.3
(2C), 43.7 (2C), 39.7 (2C), 14.7 (2C), 13.4 (2C); HRMS
(EI) Mþ; found: 412.2356. C24H32N2O4 requires: 412.2362.
3.1.32. 7,70-Diacetyl-6,60-bis((2R,3R)-3-(tert-butyldiphenyl-
silyloxy)-5-oxotetrahydrofuran-2-yl)-5,50-dihydroxy-4,40-
dimethoxy-2,20-binaphthyl-8,80-diyl diacetate (54)
To a solution of biscyanophthalide 4 (16 mg, 0.043 mmol) and
enone 39(39 mg, 0.095 mmol) in DMSO (3 mL) wasadded drop-
wiseasolutionofpotassiumtert-butoxide(10 mg, 0.086 mmol) in
DMSO (2 mL). After 10 min the orange solution was cooled in an
ice bath, diluted with diethyl ether and quenched with saturated
ammonium chloride. The mixture was decanted and the aqueous
layer was extracted three times with diethyl ether. The combined
organic layers werewashed with brine, dried over MgSO4, filtered
and concentrated in vacuo to give a yellow oil (53, 31 mg).
The crude compound 53 (31 mg, 0.027 mmol) was dissolved
in dichloromethane (2 mL) and a solution of boron trifluoride
diethyl etherate (4.1 mL, 0.033 mmol) in dichloromethane
(0.5 mL) was added at ꢁ78 ꢀC. The temperature was then raised
to 0 ꢀC over 30 min, then pyridine (0.5 mL) and acetic anhy-
dride (0.3 mL) were added and the mixture was stirred at
3.1.30. 4,40-Diformyl-5,50-dimethoxy-biphenyl-3,30-dicarb-
oxylic acid bisdiethylamide (52)
Biaryl 51 (1.65 g, 4.00 mmol) and TMEDA (3.5 mL) were
dissolved in THF (100 mL) and the solution was cooled to
ꢁ78 ꢀC. tBuLi (11 mL 1.6 M, 17.6 mmol) was added dropwise
and the mixture was stirred for 1 h. Freshly distilled DMF
(12 mL) was added and the reaction was allowed to warm slowly
to room temperature and was left to stir for 15 h. At 0e5 ꢀC the
mixture changed colour from dark brown to yellow. The mixture

O. Andrey et al. / Tetrahedron 64 (2008) 3912e3927
2. Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
3927
room temperature for 5 h. The reaction was hydrolyzed with
water and hydrochloric acid (10%) then extracted with dichloro-
methane (3ꢂ5 mL). The combined organic layers were washed
with water, brine, dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash chromatography eluting with
hexaneseethyl acetate (7:3/1:1) gave the title compound as
a yellow oil (11 mg, 23% from 4). nmax (film) 3379, 2954,
2940, 2837, 1765, 1700, 1651, 1584, 1519, 1444, 1424, 1368,
1199, 1179, 1149, 1110, 1055, 1007, 910, 820, 735 cmꢁ1; dH
(400 MHz, CDCl3) 9.51 (2H, br s, 5-OH and 50-OH), 7.73e
7.09 (24H, m, AreH), 5.86 (2H, br s, H-200 and H-2000), 5.03
(2H, br s, H-300 and H-3000), 4.18 (6H, s, 4-OMe and 40-OMe),
2.65 (6H, s, 7-COMe and 70-COMe), 2.52e2.37 (4H, m, H-400
and H-4000), 2.41 (6H, s, 8-OCOMe and 80-OCOMe), 0.82
(18H, s, 2ꢂSiMe3); dC (100 MHz, CDCl3) 201.2 (2C), 174.3
(2C), 169.2 (2C), 139.7 (6C), 135.93 (4C), 135.87 (4C), 135.0
(2C), 133.0 (2C), 132.5 (2C), 130.0 (2C), 129.6 (2C), 128.0
(4C), 127.8 (4C), 127.3 (4C), 114.5 (2C), 113.5 (4C), 105.1
(2C), 82.5 (2C), 70.5 (2C), 56.7 (2C), 38.7 (2C), 30.3 (2C),
26.4 (6C), 20.6 (2C), 18.8 (2C); MS (FABþ, m-nitrobenzylalco-
hol) 1223 (MHþ, 9), 198 (22), 197 (33), 89 (24); HRMS (FABþ)
MHþ; found: 1223.4226. C70H71O16Si2 requires: 1223.4281.
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G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 2263.
8. (a) For reviews of the HausereKraus annulation in synthesis, see:
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Acknowledgements
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We thank the Swiss National Foundation for the award of
a postdoctoral fellowship (O.A.).
16. (a) Brimble, M. A.; Stuart, S. J. J. Chem. Soc., Perkin Trans. 1 1990, 881;
(b) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem.
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References and notes
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1. For a review on the isolation and structure of pyranonaphthoquinone
antibiotics see: Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod.
Rep. 1999, 16, 267.